Methylmalonic Acidemia
Disease synonyms
Methylmalonic aciduria, MMA
Inheritance pattern
Autosomal recessive
Clinical features
Methylmalonic acidemia (MMA) is an autosomal recessive disorder of amino acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA. The prevalence of methylmalonic acidemia is estimated between 1:50,000 and 1:100,000 1, 2. In Japan, the birth prevalence may be as high as 1:50,000 3.
"Isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that results from a failure to convert methylmalonyl-CoA into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid 1.
Isolated methylmalonic academia includes following phenotypes:
- Complete or partial deficiency of the enzyme methylmalonyl-CoA mutase
- Defect in transport or synthesis of the methylmalonyl-CoA mutase cofactor, adenosyl-cobalamin
- Deficiency of the enzyme methylmalonyl-CoA epimerase
All phenotypes are characterized by periods of intermittent metabolic decompensation associated with infection or stress, and periods of health.
The major clinical features of MMA in the neonatal period include lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia, resulting in death within the first four weeks of life.
Infantile onset MMA, non-responsive for B12, presents with developing lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age.
An intermediate B12-responsive MMA phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life. Affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake.
Atypical and benign adult onset MMA phenotypes are commonly associated with increased urinary excretion of methylmalonate.
Major secondary complications of methylmalonic acidemia include: intellectual impairment, tubulointerstitial nephritis with progressive renal failure, pancreatitis, growth failure, functional immune impairment, optic nerve atrophy and metabolic stroke, e.g. basal ganglia injury which results in choreoathetosis, dystonia, and para/quadriparesis.
Diagnosis of isolated MMA relies on analysis of organic acids in plasma and/or urine, cellular biochemical studies and molecular genetic testing. In a majority of MMA-affected cases the identification of biallelic pathogenic variants in one of the five genes (MUT, MMAA, MMAB, MCEE, and MMADHC) confirms the clinical diagnosis. Recent genetic research studies have indicated that defects in additional genes may also be associated with methylmalonic acidemia (table).
| Gene | OMIM (Gene) | Associated diseases (OMIM) | Inheritance |
|---|---|---|---|
| AARS2 | 612035 | Combined oxidative phosphorylation deficiency 8; Leukoencephalopathy, progressive, with ovarian failure | AR |
| ABCA1 | 600046 | Tangier disease; HDL deficiency, type 2 | AR |
| ABCB4 | 171060 | gallbladder disease type 1; progressive familial intrahepatic cholestasis type 3; Cholestasis, intrahepatic, of pregnancy, 3 | AD, AR |
| ABCC2 | 601107 | Dubin-Johnson syndrome | AR |
| ABCC8 | 600509 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; leucine-sensitive hypoglycemia of infancy; familial hyperinsulinemic hypoglycemia type 1; transient neonatal diabetes mellitus type 2 | AD, AR |
| ABCD1 | 300371 | adrenoleukodystrophy | XLR |
| ABCD3 | 170995 | congenital bile acid synthesis defect-5 | AR |
| ABCD4 | 603214 | Methylmalonic aciduria and homocystinuria, cblJ type | AR |
| ACAD8 | 604773 | AR | |
| ACAD9 | 611103 | Acyl-Coa Dehydrogenase Family, Member 9, Deficiency Of | AR |
| ACADM | 607008 | medium chain acyl-CoA dehydrogenase deficiency | AR |
| ACADS | 606885 | short-chain acyl-CoA dehydrogenase deficiency | AR |
| ACADSB | 600301 | 2-methylbutyrylglycinuria | AR |
| ACADVL | 609575 | very long chain acyl-CoA dehydrogenase deficiency | AR |
| ACAT1 | 607809 | alpha-methylacetoacetic aciduria | AR |
| ACOX1 | 609751 | Peroxisomal acyl-CoA oxidase deficiency | AR |
| ACSF3 | 614245 | Combined malonic and methylmalonic aciduria | |
| ACY1 | 104620 | Aminoacylase 1 deficiency | AR |
| ADA | 608958 | Adenosine deaminase deficiency | AR |
| ADAMTSL2 | 612277 | Geleophysic dysplasia 1 | AR |
| ADAR | 146920 | Dyschromatosis symmetrica hereditaria; Aicardi-Goutieres syndrome type 6 | AD, AR |
| ADGRG1 | 604110 | bilateral frontoparietal polymicrogyria; bilateral perisylvian polymicrogyria | AR |
| ADK | 102750 | Hypermethioninemia due to adenosine kinase deficiency | AR |
| ADSL | 608222 | Adenylosuccinase deficiency | AR |
| AFG3L2 | 604581 | spinocerebellar ataxia 28; spastic ataxia 5 | AD, AR |
| AGA | 613228 | Aspartylglucosaminuria | AR |
| AGL | 610860 | glycogen storage disease type III | AR |
| AGPAT2 | 603100 | Lipodystrophy, congenital generalized, type 1 | AR |
| AGPS | 603051 | rhizomelic chondrodysplasia punctata type 3 | AR |
| AGXT | 604285 | primary hyperoxaluria type 1 | AR |
| AHCY | 180960 | Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase | AR |
| AIFM1 | 300169 | Deafness, X-linked 5; Combined oxidative phosphorylation deficiency 6; Cowchock syndrome | XLR |
| AIMP1 | 603605 | hypomyelinating leukodystrophy-3 | AR |
| AKT2 | 164731 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Hypoinsulinemic hypoglycemia with hemihypertrophy | AD |
| ALAD | 125270 | Acute hepatic porphyria | AR |
| ALAS2 | 301300 | X-linked sideroblastic anemia; Protoporphyria, erythropoietic, X-linked | XL, XLR |
| ALDH3A2 | 609523 | Sjogren-Larsson syndrome | AR |
| ALDH4A1 | 606811 | hyperprolinemia, type II | AR |
| ALDH5A1 | 610045 | Succinic semialdehyde dehydrogenase deficiency | AR |
| ALDH7A1 | 107323 | pyridoxine-dependent epilepsy | AR |
| ALDOA | 103850 | Glycogen storage disease XII | AR |
| ALDOB | 612724 | hereditary fructose intolerance | AR |
| ALG1 | 605907 | congenital disorder of glycosylation type 1k | AR |
| ALG11 | 613666 | congenital disorder of glycosylation type 1p | AR |
| ALG12 | 607144 | congenital disorder of glycosylation type 1g | AR |
| ALG13 | 300776 | congenital disorder of glycosylation type 1s | XLD |
| ALG2 | 607905 | congenital disorder of glycosylation type 1i | AR |
| ALG3 | 608750 | congenital disorder of glycosylation type 1d | AR |
| ALG6 | 604566 | congenital disorder of glycosylation type 1c | AR |
| ALG8 | 608103 | congenital disorder of glycosylation type 1h | AD, AR |
| ALG9 | 606941 | Gillessen-Kaesbach-Nishimura syndrome; congenital disorder of glycosylation type 1l | AR |
| ALPL | 171760 | adult hypophosphatasia; infantile hypophosphatasia; childhood-onset hypophosphatasia | AD, AR |
| AMN | 605799 | AR | |
| AMT | 238310 | glycine encephalopathy | AR |
| ANK1 | 612641 | Spherocytosis, type 1 | AD, AR |
| ANTXR2 | 608041 | Hyaline fibromatosis syndrome | AR |
| AP3B1 | 603401 | Hermansky-Pudlak syndrome type 2 | AR |
| AP4B1 | 607245 | spastic paraplegia 47 | AR |
| AP4E1 | 607244 | spastic paraplegia 51 | AD, AR |
| AP4M1 | 602296 | autosomal recessive spastic paraplegia type 50 | AR |
| AP4S1 | 607243 | spastic paraplegia 52 | AR |
| APOA5 | 606368 | HYPERLIPOPROTEINEMIA, TYPE V; Hypertriglyceridemia, susceptibility to | AD |
| APOB | 107730 | Hypercholesterolemia, Type B; Hypobetalipoproteinemia | AD, AR |
| APOC2 | 608083 | Apolipoprotein C-Ii Deficiency | AR |
| APOE | 107741 | Alzheimer Disease 2; Sea-blue histiocyte disease; Macular Degeneration, Age-Related, 1; early-onset familial Alzheimer disease-3; Lipoprotein glomerulopathy | AD, AR |
| APP | 104760 | Alzheimer Disease; Cerebral Amyloid Angiopathy, App-Related | AD |
| APTX | 606350 | Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia | AR |
| ARG1 | 608313 | Argininemia | AR |
| ARSA | 607574 | metachromatic leukodystrophy | AR |
| ARSB | 611542 | mucopolysaccharidosis type VI | AR |
| ASAH1 | 613468 | Spinal muscular atrophy with progressive myoclonic epilepsy; Farber lipogranulomatosis | AR |
| ASL | 608310 | argininosuccinic aciduria | AR |
| ASPA | 608034 | Canavan disease | AR |
| ASS1 | 603470 | citrullinemia | AR |
| ATM | 607585 | familial breast-ovarian cancer type 2; ataxia-telangiectasia | AD, AR |
| ATP13A2 | 610513 | Kufor-Rakeb syndrome; spastic paraplegia type 78 | AR |
| ATP6V0A2 | 611716 | autosomal recessive cutis laxa type IIA; Wrinkly skin syndrome | AR |
| ATP7A | 300011 | X-linked distal spinal muscular atrophy type 3; Occipital horn syndrome; Menkes disease | XLR |
| ATP7B | 606882 | Wilson disease | AR |
| ATPAF2 | 608918 | Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1 | AR |
| AUH | 600529 | 3-methylglutaconic aciduria, type I | AR |
| B3GALNT2 | 610194 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A11 | AR |
| B4GALT1 | 137060 | congenital disorder of glycosylation type 2d | AR |
| BCAP31 | 300398 | Deafness, dystonia, and cerebral hypomyelination; ddch contiguous abcd1/dxs1375e deletion syndrome, included; cadds, included | XLR |
| BCKDHA | 608348 | maple syrup urine disease type Ia; maple syrup urine disease type Ib; maple syrup urine disease type II | AR |
| BCKDHB | 248611 | maple syrup urine disease type Ia; maple syrup urine disease type Ib; maple syrup urine disease type II | AR |
| BCS1L | 603647 | Mitochondrial complex III deficiency, nuclear type 1; Leigh syndrome; Bjornstad syndrome; GRACILE syndrome | AR, M |
| BEST1 | 607854 | vitelliform macular dystrophy-2; vitreoretinochoroidopathy; Bestrophinopathy, autosomal recessive; Retinitis pigmentosa 50 | AD |
| BLK | 191305 | MODY type 11 | AD |
| BOLA3 | 613183 | Multiple mitochondrial dysfunctions syndrome 2 | AR |
| BRAT1 | 614506 | Rigidity and multifocal seizure syndrome, lethal neonatal; neurodevelopmental disorder with cerebellar atrophy and with or without seizures | AR |
| BSCL2 | 606158 | Lipodystrophy, congenital generalized, type 2; spastic paraplegia 17; Neuropathy, distal hereditary motor, type V; Encephalopathy, progressive, with or without lipodystrophy | AD, AR |
| BTD | 609019 | biotinidase deficiency | AR |
| C12orf65 | 613541 | Combined oxidative phosphorylation deficiency 7 | AR |
| C19orf12 | 614297 | neurodegeneration with brain iron accumulation 4; spastic paraplegia 43 | AD, AR |
| CA5A | 114761 | Hyperammonemia due to carbonic anhydrase VA deficiency | AR |
| CASP10 | 601762 | Autoimmune lymphoproliferative syndrome, type II; Lymphoma, non-Hodgkin; Gastric Cancer | AD |
| CASP8 | 601763 | familial breast-ovarian cancer type 2; Hepatocellular Carcinoma; Lung Cancer | AD, AR |
| CAV1 | 601047 | AD, AR | |
| CAVIN1 | 603198 | Lipodystrophy, congenital generalized, type 4 | AR |
| CBLIF | 609342 | Intrinsic factor deficiency | AR |
| CBS | 613381 | homocystinuria with or without response to pyridoxine | AR |
| CD320 | 606475 | Methylmalonic aciduria due to transcobalamin receptor defect | |
| CEL | 114840 | MODY type 8 | AD |
| CERS1 | 606919 | Progressive myoclonic epilepsy-8 | AR |
| CIDEC | 612120 | Lipodystrophy, familial partial, type 5 | AR |
| CISD2 | 611507 | Wolfram syndrome 2 | AR |
| CLCN2 | 600570 | Epilepsy, Idiopathic Generalized, Susceptibility To, 11; Leukoencephalopathy with ataxia | AD, AR |
| CLN3 | 607042 | neuronal ceroid lipofuscinosis type 3 | AR |
| CLN5 | 608102 | neuronal ceroid lipofuscinosis type 5 | AR |
| CLN6 | 606725 | adulte onset neuronal ceroid lipofuscinosis, Kufs type; neuronal ceroid lipofuscinosis type 6 | AR |
| CLN8 | 607837 | neuronal ceroid lipofuscinosis type 8; neuronal ceroid lipofuscinosistype 8, Northern epilepsy variant | AR |
| CLPB | 616254 | 3-methylglutaconic aciduria type VII with cataracts, neurologic involvement and neutropenia | AR |
| CLPP | 601119 | Perrault syndrome 3 | AR |
| COA8 | 616003 | Mitochondrial complex IV deficiency | AR, M |
| COASY | 609855 | Neurodegeneration with brain iron accumulation 6; Pontocerebellar hypoplasia type 12 | AR |
| COG1 | 606973 | Congenital disorder of glycosylation, type IIg | AR |
| COG4 | 606976 | congenital disorder of glycosylation type 2j; Saul-Wilson syndrome | AD, AR |
| COG5 | 606821 | Congenital disorder of glycosylation, type IIi | AR |
| COG6 | 606977 | congenital disorder of glycosylation type 2l; Shaheen syndrome | AR |
| COG7 | 606978 | Congenital disorder of glycosylation, type IIe | AR |
| COG8 | 606979 | congenital disorder of glycosylation type 2h | |
| COL11A2 | 120290 | Stickler syndrome, type III; Otospondylomegaepiphyseal dysplasia; Deafness, autosomal dominant 13; Deafness, autosomal recessive 53; Fibrochondrogenesis 2 | AD, AR |
| COL2A1 | 120140 | Epiphyseal dysplasia, multiple, with myopia and deafness; Legg-Calve-Perthes disease; Platyspondylic skeletal dysplasia, Torrance type; Kniest dysplasia; congenital spondyloepiphyseal dysplasia; SMED Strudwick type; Achondrogenesis, type II or hypochondrogenesis; Spondyloperipheral dysplasia; Osteoarthritis with mild chondrodysplasia; Avascular necrosis of the femoral head; Czech dysplasia; Stickler syndrome type 1; Stanescu type spondyloepiphyseal dysplasia | AD |
| COL4A1 | 120130 | porencephaly 1; Brain small vessel disease with or without ocular anomalies; Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps; Hemorrhage, intracerebral, susceptibility to | AD |
| COL4A2 | 120090 | Brain small vessel disease type 2; Hemorrhage, intracerebral, susceptibility to | AD |
| COQ2 | 609825 | Multiple system atrophy, susceptibility to; Coenzyme Q10 deficiency, primary, 1 | AD, AR |
| COQ8A | 606980 | primary Coenzyme Q10 deficiency type 4 - COQ10D4 | AR |
| COQ9 | 612837 | Coenzyme Q10 deficiency, primary, 5 | AR |
| COX10 | 602125 | Mitochondrial complex IV deficiency; Leigh syndrome | AR, M |
| COX15 | 603646 | Leigh syndrome; Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 | AR, M |
| COX20 | 614698 | Mitochondrial complex IV deficiency | AR, M |
| COX6B1 | 124089 | Mitochondrial complex IV deficiency | AR, M |
| CP | 117700 | aceruloplasminemia | AR |
| CPOX | 612732 | Coproporphyria, hereditary | AD, AR |
| CPS1 | 608307 | carbamoyl-phosphate synthetase 1 deficiency | AR |
| CPT1A | 600528 | hepatic CPT deficiency type IA | AR |
| CPT2 | 600650 | stress-induced myopathic CPT II deficiency; infantile CPT deficiency; lethal neonatal CPT II deficiency; susceptibility to infection-induced acute encephalopathy type 4 | AD, AR |
| CSF1R | 164770 | hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia | AD, AR |
| CTC1 | 613129 | Cerebroretinal microangiopathy with calcifications and cysts | AR |
| CTH | 607657 | Cystathioninuria | AR |
| CTLA4 | 123890 | systemic lupus erythematosus; Autoimmune lymphoproliferative syndrome, type V | AD |
| CTNS | 606272 | ocular nonnephropathic cystinosis; cystinosis; late-onset juvenile or adolescent nephropathic cystinosis | AR |
| CTSA | 613111 | galactosialidosis | AR |
| CTSC | 602365 | Papillon-Lefevre syndrome | AR |
| CTSD | 116840 | neuronal ceroid lipofuscinosis type 10 | AR |
| CTSF | 603539 | neuronal ceroid lipofuscinosis type 13 | AR |
| CTSK | 601105 | pycnodysostosis | AR |
| CUBN | 602997 | megaloblastic anemia 1 | AR |
| CYP11B1 | 610613 | Glucocorticoid-Remediable Aldosteronism; Adrenal Hyperplasia, Congenital, Due To Steroid 11-Beta-Hydroxylase Deficiency | AD, AR |
| CYP17A1 | 609300 | congenital adrenal hyperplasia due to 17-Alpha-Hydroxylase deficiency | AR |
| CYP19A1 | 107910 | Aromatase excess syndrome; Aromatase deficiency | AD |
| CYP21A2 | 613815 | congenital adrenal hyperplasia type 1 | AR |
| CYP27A1 | 606530 | cerebrotendinous xanthomatosis | AR |
| CYP2U1 | 610670 | spastic paraplegia 56 | AR |
| CYP7B1 | 603711 | spastic paraplegia 5A | AR |
| D2HGDH | 609186 | D-2-Hydroxyglutaric Aciduria 1 | AR |
| DAG1 | 128239 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type C9 | AR |
| DARS2 | 610956 | leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation | AR |
| DBT | 248610 | maple syrup urine disease type Ia; maple syrup urine disease type Ib; maple syrup urine disease type II | AR |
| DCAF17 | 612515 | Woodhouse-Sakati syndrome | AR |
| DDC | 107930 | Aromatic L-amino acid decarboxylase deficiency | AR |
| DDOST | 602202 | Congenital disorder of glycosylation, type Ir | AR |
| DGUOK | 601465 | mitochondrial DNA depletion syndrome 3 | AR |
| DHCR7 | 602858 | Smith-Lemli-Opitz syndrome | AR |
| DHDDS | 608172 | retinitis pigmentosa type 59; Developmental delay and seizures with or without movement abnormalities | AD, AR |
| DIABLO | 605219 | Deafness, autosomal dominant 64 | AD |
| DKC1 | 300126 | X-linked dyskeratosis congenita | XLR |
| DLAT | 608770 | Pyruvate dehydrogenase E2 deficiency | AR |
| DLD | 238331 | dihydrolipoamide dehydrogenase deficiency | AR |
| DNAJC5 | 611203 | neuronal ceroid lipofuscinosis type 4, Parry type | AD |
| DNM1L | 603850 | Encephalopahty, lethal, due to defective mitochondrial peroxisomal fission | AD, AR |
| DOLK | 610746 | congenital disorder of glycosylation type 1m | AR |
| DPM1 | 603503 | Congenital disorder of glycosylation, type Ie | AR |
| DPM2 | 603564 | Congenital disorder of glycosylation, type Iu | AR |
| DPM3 | 605951 | congenital disorder of glycosylation, type Io | AR |
| DPYD | 612779 | Dihydropyrimidine dehydrogenase deficiency | AR |
| DYM | 607461 | Dyggve-Melchior-Clausen disease | AR |
| EARS2 | 612799 | Combined oxidative phosphorylation deficiency 12 | AR |
| ECHS1 | 602292 | mitochondrial short-chain enoyl-CoA hydratase 1 deficiency | AR |
| EIF2AK3 | 604032 | Wolcott-Rallison syndrome | AR |
| EIF2B1 | 606686 | leukoencephaly with vanishing white matter | AR |
| EIF2B2 | 606454 | leukoencephaly with vanishing white matter | AR |
| EIF2B3 | 606273 | leukoencephaly with vanishing white matter | AR |
| EIF2B4 | 606687 | leukoencephaly with vanishing white matter | AR |
| EIF2B5 | 603945 | leukoencephaly with vanishing white matter | AR |
| ENO3 | 131370 | Glycogen storage disease XIII | AR |
| ENPP1 | 173335 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Arterial calcification, generalized, of infancy, 1; OBESITY; Hypophosphatemic rickets, autosomal recessive, 2; Cole disease | AD, AR |
| EPB42 | 177070 | Spherocytosis, type 5 | |
| EPHX2 | 132811 | familial hypercholesterolemia | AD |
| EPM2A | 607566 | Epilepsy, progressive myoclonic 2A (Lafora); Epilepsy, progressive myoclonic 2B (Lafora) | AR |
| ERCC6 | 609413 | Cockayne syndrome, type B; Lung Cancer; Cerebrooculofacioskeletal syndrome 1 | AD, AR |
| ETFA | 608053 | multiple acyl-CoA dehydrogenase deficiency | AR |
| ETFB | 130410 | multiple acyl-CoA dehydrogenase deficiency | AR |
| ETFDH | 231675 | multiple acyl-CoA dehydrogenase deficiency | AR |
| ETHE1 | 608451 | ethylmalonic encephalopathy | AR |
| F2 | 176930 | thrombophilia due to thrombin defect; susceptibility to ischemic stroke; congenital prothrombin deficiency; susceptibility to recurrent pregnancy loss type 2 | AD, AR |
| F5 | 612309 | thrombophilia due to activated protein C resistance; factor V deficiency; Budd-Chiari syndrome; susceptibility to ischemic stroke; susceptibility to recurrent pregnancy loss type 1 | AD, AR |
| FA2H | 611026 | spastic paraplegia 35 | AR |
| FADD | 602457 | recurrent infections with encephalopathy, hepatic dysfunction and cardiovasuclar malformations | AR |
| FAH | 613871 | tyrosinemia type 1 | AR |
| FAM126A | 610531 | hypomyelinating leukodystrophy-5 | AR |
| FARS2 | 611592 | Combined oxidative phosphorylation deficiency 14; spastic paraplegia type 77 | AR |
| FAS | 134637 | Autoimmune lymphoproliferative syndrome | AD |
| FASLG | 134638 | Lung Cancer; Autoimmune lymphoproliferative syndrome | AD |
| FASTKD2 | 612322 | AR | |
| FBN1 | 134797 | Marfan syndrome; stiff skin syndrome; Weill-Marchesani syndrome 2; geleophysic dysplasia 2; Marfan lipodystrophy syndrome | AD |
| FBP1 | 611570 | Fructose-1,6-bidphosphatase deficiency | AR |
| FBXL4 | 605654 | mitochondrial DNA depletion syndrome 13 | AR |
| FECH | 612386 | Protoporphyria, erythropoietic, autosomal recessive | AR |
| FGF23 | 605380 | Hypophosphatemic rickets, autosomal dominant | AD, AR |
| FH | 136850 | Leiomyomatosis and renal cell cancer; Fumarase deficiency | AD, AR |
| FHL1 | 300163 | Scapuloperoneal myopathy, X-linked dominant; Myopathy, X-linked, with postural muscle atrophy; Emery-Dreifuss muscular dystrophy 6; Myopathy, Reducing Body, X-Linked, Early-Onset, Severe; Myopathy, reducing body, X-linked, childhood-onset | XL, XLD, XLR |
| FOLR1 | 136430 | cerebral folate transport deficiency | AR |
| FOXP3 | 300292 | Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked | XLR |
| FOXRED1 | 613622 | AR | |
| FTL | 134790 | Hyperferritinemia With Or Without Cataract; neurodegeneration with brain iron accumulation 3 | AD, AR |
| FUCA1 | 612280 | fucosidosis | AR |
| G6PC | 613742 | glycogen storage disease type IA | AR |
| G6PD | 305900 | glucose-6-phosphate dehydrogenase deficiency; resistance to malaria | XLD |
| GAA | 606800 | Pompe disease | AR |
| GALC | 606890 | Krabbe disease | AR |
| GALE | 606953 | Galactose epimerase deficiency | AR |
| GALK1 | 604313 | galactokinase deficiency | AR |
| GALNS | 612222 | mucopolysaccharidosis type IVA | AR |
| GALT | 606999 | galactosemia | AR |
| GAMT | 601240 | guanidinoacetate methyltransferase deficiency | AR |
| GAN | 605379 | giant axonal neuropathy | AR |
| GATA6 | 601656 | Tetralogy of Fallot; Conotruncal Heart Malformations; Pancreatic agenesis and congenital heart defects; Atrioventricular septal defect 5; Atrial septal defect 9 | AD |
| GATM | 602360 | Cerebral creatine deficiency syndrome 3 | AD, AR |
| GBA | 606463 | Lewy body dementia; Susceptibility to late-onset Parkinson disease; Gaucher disease type 1; Gaucher disease type 2 (acute); Gaucher disease type 3 (subacute/ chronic); Gaucher disease, cardiovascular form; Gaucher disease, perinatal-lethal form | AD, AR |
| GBE1 | 607839 | storage disease type 4; Polyglucosan body disease, adult form | AR |
| GCDH | 608801 | glutaric academia type I | AR |
| GCK | 138079 | MODY type 2; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Hyperinsulinemic hypoglycemia, familial, 3; permanent neonatal diabetes mellitus | AD, AR |
| GCSH | 238330 | glycine encephalopathy | AR |
| GFAP | 137780 | Alexander disease | AD |
| GFER | 600924 | Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay | |
| GFM1 | 606639 | Combined oxidative phosphorylation deficiency 1 | AR |
| GFM2 | 606544 | AR | |
| GFPT1 | 138292 | congenital myasthenic syndrome with tubular aggregates type 1 | AR |
| GHR | 600946 | familial hypercholesterolemia; Laron syndrome; Increased responsiveness to growth hormone | AD, AR |
| GJA1 | 121014 | Oculodentodigital dysplasia | AD, AR |
| GJB1 | 304040 | Charcot-Marie-Tooth disease type 1 | XLD |
| GJC2 | 608803 | Leukodystrophy, hypomyelinating, 2; spastic paraplegia 44 | AD, AR |
| GK | 300474 | Glycerol kinase deficiency | XLR |
| GLA | 300644 | Fabry disease; Fabry disease, atypical cardiac variant | XL |
| GLB1 | 611458 | GM1-gangliosidosis; GM1-gangliosidosis type II; GM1-gangliosidosis type III; mucopolysaccharidosis type IVB | AR |
| GLDC | 238300 | glycine encephalopathy | AR |
| GLIS3 | 610192 | Diabetes mellitus, neonatal, with congenital hypothyroidism | AR |
| GLRX5 | 609588 | Anemia, sideroblastic, 3, pyridoxine-refractory | AR |
| GLUD1 | 138130 | familial hyperinsulinemic hypoglycemia-6 | AD |
| GLUL | 138290 | Glutamine deficiency, congenital | AR |
| GM2A | 613109 | GM2-gangliosidosis, AB variant | AR |
| GMPPA | 615495 | Alacrima, achalasia, and mental retardation syndrome | AR |
| GNE | 603824 | Sialuria; Nonaka myopathy | AD, AR |
| GNMT | 606628 | AR | |
| GNPAT | 602744 | rhizomelic chondrodysplasia punctata type 2 | AR |
| GNPTAB | 607840 | mucolipidosis II alpha/beta; mucolipidosis III alpha/beta | AR |
| GNPTG | 607838 | mucolipidosis III gamma | AR |
| GNS | 607664 | mucopolysaccharidosis type IIID | AR |
| GOSR2 | 604027 | Epilepsy, progressive myoclonic 6 | AR |
| GPC3 | 300037 | Wilms tumor, type 1; Simpson-Golabi-Behmel syndrome, type 1 | XLR |
| GRN | 138945 | frontotemporal lobar degeneration with ubiquitin-positive inclusions; neuronal ceroid lipofuscinosis type 11 | AD, AR |
| GTPBP3 | 608536 | Combined oxidative phosphorylation deficiency 23 | AR |
| GUSB | 611499 | mucopolysaccharidosis type VII | AR |
| GYG1 | 603942 | Glycogen storage disease XV; Polyglucosan body myopathy 2 | AR |
| GYS1 | 138570 | Glycogen storage disease 0, muscle | AR |
| GYS2 | 138571 | Glycogen storage disease 0, liver | AR |
| HADH | 601609 | 3-hydroxyacyl-CoA dehydrogenase deficiency; familial hyperinsulinemic hypoglycemia type 4 | AR |
| HADHA | 600890 | mitochondrial trifunctional protein deficiency; long-chain 3-hydroxyl-CoA dehydrogenase deficiency | AR |
| HADHB | 143450 | mitochondrial trifunctional protein deficiency | AR |
| HAMP | 606464 | Hemochromatosis, type 2B | AR |
| HCFC1 | 300019 | mental retardation 3 | XLR |
| HEPACAM | 611642 | megalencephalic leukoencephalopathy with subcortical cysts type 2A; megalencephalic leukoencephalopathy with subcortical cysts type 2B, remitting, with or without mental retardation | AD, AR |
| HEXA | 606869 | Tay-Sachs disease/ GM2-gangliosidosis | AR |
| HEXB | 606873 | Sandhoff disease | AR |
| HFE | 613609 | Alzheimer Disease; hepatoerythropoietic porphyria; variegate porphyria; hemochromatosis type 1; susceptibility to microvascular complications of diabetes type 7; Transferrin serum level QTL2 | AD, AR |
| HGD | 607474 | Alkaptonuria | AR |
| HGSNAT | 610453 | mucopolysaccharidosis type IIIC; retinitis pigmentosa type 73 | AR |
| HIBCH | 610690 | 3-hydroxyisobutryl-CoA hydrolase deficiency | AR |
| HJV | 608374 | hemochromatosis type 2A | AR |
| HLCS | 609018 | Holocarboxylase synthetase deficiency | AR |
| HMBS | 609806 | acute intermittent porphyria | AD |
| HMGCL | 613898 | HMG-CoA lyase deficiency | AR |
| HMGCS2 | 600234 | HMG-CoA synthase-2 deficiency | AR |
| HNF1A | 142410 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Renal carcinoma, chromophobe, somatic; Diabetes mellitus, insulin-dependent-1; MODY type 3 | AD, AR |
| HNF1B | 189907 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 5; Renal carcinoma, chromophobe, somatic | AD |
| HNF4A | 600281 | MODY type 1; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young | AD |
| HPD | 609695 | Tyrosinemia, type III | AD, AR |
| HPRT1 | 308000 | Lesch-Nyhan syndrome; Kelley-Seegmiller syndrome | XLR |
| HRAS | 190020 | Bladder Cancer; Melanocytic nevus syndrome, congenital, somatic; Nevus, Epidermal; Schimmelpenning-Feuerstein-Mims Syndrome; Thyroid Carcinoma, Follicular; Costello syndrome | AD |
| HSD17B10 | 300256 | HSD10 mitochondrial disease | XLD |
| HSD17B4 | 601860 | Perrault syndrome type 1; D-bifunctional protein deficiency | AR |
| HSD3B2 | 613890 | 3-beta-hydroxysteroid dehydrogenase 2 deficiency | AR |
| HSPD1 | 118190 | spastic paraplegia 13; hypomyelinating leukodystrophy-4 | AD, AR |
| HTRA1 | 602194 | Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 | AD, AR |
| HYAL1 | 607071 | Mucopolysaccharidosis type IX | AR |
| IARS2 | 612801 | Cataracts, Growth Hormone Deficiency, sensory neuropathy, sensorineural hearing loss, skeletal dysplasia | AR |
| IBA57 | 615316 | Multiple mitochondrial dysfunctions syndrome 3 | AR |
| IDS | 300823 | mucopolysaccharidosis type II | XLR |
| IDUA | 252800 | mucopolysaccharidosis type IH; mucopolysaccharidosis type 1; mucopolysaccharidosis type IS | AR |
| IER3IP1 | 609382 | Microcephaly, epilepsy, and diabetes syndrome | AR |
| IFIH1 | 606951 | Singleton-Merten syndrome type 1; Aicardi-Goutieres syndrome 7 | AD |
| INS | 176730 | Diabetes Mellitus, Insulin-Dependent, 2; MODY type 10 | AD, AR |
| INSR | 147670 | Donohue syndrome; Rabson-Mendenhall syndrome; Hyperinsulinemic hypoglycemia, familial, 5; Diabetes mellitus, insulin-resistant, with acanthosis nigricans | AD, AR |
| ISCA2 | 615317 | Multiple mitochondrial dysfunctions syndrome type 4 | AR |
| ITK | 186973 | Lymphoproliferative syndrome 1 | AR |
| IVD | 607036 | isovaleric acidemia | AR |
| JAG1 | 601920 | Alagille syndrome; Tetralogy of Fallot | AD |
| JAM3 | 606871 | Hemorrhagic destruction of the brain, subpendymal calcification, and cataracts | AR |
| KCNC1 | 176258 | Progressive myoclonic epilepsy 7 | AD |
| KCNJ10 | 602208 | autosomal recessive deafness type 4 with enlarged vestibular aqueduct; Seizures, Sensorineural Deafness, Ataxia, Mental Retardation, And Electrolyte Imbalance | AR |
| KCNJ11 | 600937 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; familial hyperinsulinemic hypoglycemia type 2; transient neonatal diabetes mellitus type 3; MODY type 13 | AD, AR |
| KCNT1 | 608167 | early infantile epileptic encephalopathy 14; nocturnal frontal lobe epilepsy 5 | AD |
| KCTD7 | 611725 | progressive myoclonic epilepsy type 3 with or without intracellular inclusions | AR |
| KIF5A | 602821 | spastic paraplegia 10; Neonatal intractable myoclonus | AD |
| KLF11 | 603301 | MODY type 7 | |
| KRAS | 190070 | Arteriovenous malformations of the brain; Bladder Cancer; familial breast-ovarian cancer type 2; Gastric Cancer, Hereditary Diffuse; Schimmelpenning-Feuerstein-Mims Syndrome; Lung Cancer; Pancreatic Cancer; acute myeloid leukemia; Noonan syndrome 3; Autoimmune lymphoproliferative syndrome type IV; Cardiofaciocutaneous syndrome 2 | AD |
| L2HGDH | 609584 | L-2-hydroxyglutaric aciduria | AR |
| LAMA2 | 156225 | congenital muscular dystrophy type 1A; limb-girdle Muscular dystrophy type 23 | AR |
| LAMB1 | 150240 | lissencephaly 5 | AR |
| LAMP2 | 309060 | Danon disease | XLD |
| LARGE1 | 603590 | congenital muscular dystrophy-dystroglycanopathy with mental retardation type B6; congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A6 | AR |
| LDB3 | 605906 | dilated cardiomyopathy-1C; Myopathy, myofibrillar, 4 | AD |
| LDHA | 150000 | Glycogen storage disease XI | AR |
| LDLR | 606945 | familial hypercholesterolemia | AD |
| LDLRAP1 | 605747 | Hypercholesterolemia, Autosomal Recessive | AR |
| LIAS | 607031 | Pyruvate dehydrogenase lipoic acid synthetase deficiency | AR |
| LIPA | 613497 | Wolman disease / cholesteryl ester storage disease | AR |
| LIPE | 151750 | Lipodystrophy, familial partial, type 6 | AR |
| LIPT1 | 610284 | Lipoyltransferase 1 deficiency | AR |
| LMBRD1 | 612625 | Methylmalonic aciduria and homocystinuria, cblF type | AR |
| LMNA | 150330 | dilated cardiomyopathy-1A; Lipodystrophy, familial partial, 2; Hutchinson-Gilford progeria; limb-girdle muscular dystrophy type 1B; Emery-Dreifuss muscular dystrophy 2; Malouf syndrome; Mandibuloacral dysplasia; Restrictive dermopathy, lethal; type 2B1 Charcot-Marie-Tooth disease; Heart-hand syndrome, Slovenian type; Muscular dystrophy, congenital; Emery-Dreifuss muscular dystrophy 3, AR | AD, AR |
| LMNB1 | 150340 | Leukodystrophy, adult-onset, autosomal dominant | AD |
| LPIN1 | 605518 | Myoglobinuria, acute recurrent, autosomal recessive | AR |
| LPL | 609708 | familial combined hyperlipidemia; lipoprotein lipase deficiency | AD, AR |
| LRPPRC | 607544 | Leigh syndrome, French-Canadian type | AR |
| LYRM7 | 615831 | Mitochondrial complex III deficiency nuclear type 8 | AR |
| LYST | 606897 | Chediak-Higashi syndrome | AR |
| MAGT1 | 300715 | Immunodeficiency, X-Linked, With Magnesium Defect, Epstein-Barr Virus Infection, And Neoplasia | XLR |
| MAN1B1 | 604346 | MENTAL RETARDATION, AUTOSOMAL RECESSIVE 15 | AR |
| MAN2B1 | 609458 | alpha-mannosidosis | AR |
| MANBA | 609489 | Mannosidosis, Beta A, Lysosomal | AR |
| MARS2 | 609728 | AR | |
| MCCC1 | 609010 | 3-Methylcrotonyl-CoA carboxylase 1 deficiency | AR |
| MCCC2 | 609014 | 3-methylcrotonyl-CoA carboxylase 2 deficiency | AR |
| MCEE | 608419 | Methylmalonyl-coa epimerase deficiency | AR |
| MCOLN1 | 605248 | Mucolipidosis type IV | AR |
| MFSD8 | 611124 | neuronal ceroid lipofuscinosis type 7; macular dystrophy with central cone involvement | AR |
| MGAT2 | 602616 | Congenital disorder of glycosylation, type IIa | AR |
| MGME1 | 615076 | mitochondrial DNA depletion syndrome 11 | AR |
| MLC1 | 605908 | megalencephalic leukoencephalopathy with subcortical cysts type 1 | AR |
| MLPH | 606526 | Griscelli syndrome, type 3 | AR |
| MLYCD | 606761 | Malonyl-CoA decarboxylase deficiency | AR |
| MMAA | 607481 | methylmalonic aciduria (MMA) of the cblA complementation type | AR |
| MMAB | 607568 | methylmalonic aciduria (MMA) of the cblB complementation type | AR |
| MMACHC | 609831 | Methylmalonic aciduria and homocystinuria, cblC type, digenic type included | AR |
| MMADHC | 611935 | methylmalonic aciduria (MMA) of the cblD complementation type | AR |
| MMUT | 609058 | complete deficiency of methylmalonyl-CoA mutase | AR |
| MOCS1 | 603707 | molybdenum cofactor deficiency of complementation group A | AR |
| MOCS2 | 603708 | molybdenum cofactor deficiency of complementation group B | AR |
| MOGS | 601336 | congenital disorder of glycosylation type 2b | AR |
| MPDU1 | 604041 | congenital disorder of glycosylation type 1f | AR |
| MPI | 154550 | congenital disorder of glycosylation type 1b | AR |
| MPV17 | 137960 | mitochondrial DNA depletion syndrome type 6 | AR |
| MRPL44 | 611849 | combined oxidative phosphorylation deficiency type 16 | AR |
| MRPS22 | 605810 | Combined oxidative phosphorylation deficiency 5 | AR |
| MTFMT | 611766 | Combined oxidative phosphorylation deficiency 15 | AR |
| MTHFR | 607093 | schizophrenia; thrombophilia due to thrombin defect; homocystinuria due to MTHFR deficiency; folate-sensitive neural tube defects | AD, AR |
| MTR | 156570 | homocystinuria-megaloblastic anemia, cblG complementation type; folate-sensitive neural tube defects | AR |
| MTRR | 602568 | Homocystinuria-Megaloblastic Anemia, Cble Complementation Type; folate-sensitive neural tube defects | AR |
| MYO5A | 160777 | Griscelli syndrome, type 1 | AR |
| MYOT | 604103 | Myopathy, spheroid body; Myopathy, myofibrillar, 3; limb-girdle muscular dystrophy type 1A | AD |
| NAGA | 104170 | Schindler disease, type I, III | AR |
| NAGLU | 609701 | mucopolysaccharidosis type IIIB; ? axonal Charcot-Marie-Tooth disease type 2V | AD, AR |
| NAGS | 608300 | N-acetylglutamate synthase deficiency | AR |
| NARS2 | 612803 | Combined oxidative phosphorylation deficiency 24 | AR |
| NBAS | 608025 | Short stature, optic nerve atrophy, and Pelger-Huet anomaly; Infantile liver failure syndrome type 2 | AR |
| NDUFA1 | 300078 | XLR | |
| NDUFA10 | 603835 | AR | |
| NDUFA11 | 612638 | AR | |
| NDUFA12 | 614530 | Mitochondrial complex I deficiency nuclear type 23 | AR |
| NDUFA2 | 602137 | AR | |
| NDUFA9 | 603834 | AR | |
| NDUFAF1 | 606934 | AR | |
| NDUFAF2 | 609653 | Mitochondrial complex I deficiency nuclear type 10 | AR |
| NDUFAF4 | 611776 | AR | |
| NDUFAF5 | 612360 | AR | |
| NDUFAF6 | 612392 | AR | |
| NDUFS1 | 157655 | AR | |
| NDUFS2 | 602985 | AR | |
| NDUFS3 | 603846 | AR | |
| NDUFS4 | 602694 | mitochondrial complex I deficiency | AR |
| NDUFS6 | 603848 | AR | |
| NDUFS7 | 601825 | Mitochondrial complex I deficiency, nuclear type 3 | AR |
| NDUFS8 | 602141 | AR | |
| NDUFV1 | 161015 | AR | |
| NDUFV2 | 600532 | AR | |
| NEU1 | 608272 | neuraminidase deficiency | AR |
| NEUROD1 | 601724 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 6 | AD |
| NEUROG3 | 604882 | Diarrhea 4, malabsorptive, congenital | AR |
| NFU1 | 608100 | Multiple mitochondrial dysfunctions syndrome 1 | AR |
| NGLY1 | 610661 | Congenital disorder of deglycosylation | AR |
| NHLRC1 | 608072 | Epilepsy, progressive myoclonic 2A (Lafora); Epilepsy, progressive myoclonic 2B (Lafora) | AR |
| NOTCH3 | 600276 | CADASIL; Lateral meningocele syndrome | AD |
| NPC1 | 607623 | Niemann-Pick disease type C/D | AR |
| NPC2 | 601015 | Niemann-Pick disease type C2 | AR |
| NRAS | 164790 | colorectal cancer; Melanocytic nevus syndrome, congenital, somatic; Nevus, Epidermal; Schimmelpenning-Feuerstein-Mims Syndrome; Thyroid Carcinoma, Follicular; Neurocutaneous melanosis, somatic; Noonan syndrome 6; Autoimmune lymphoproliferative syndrome type IV | AD |
| NUBPL | 613621 | AR | |
| OAT | 613349 | Gyrate atrophy of choroid and retina with or without ornithinemia | AR |
| OCLN | 602876 | Band-like calcification with simplified gyration and polymicrogyria | AR |
| OCRL | 300535 | Dent disease type 2; Lowe oculocerebrorenal syndrome | XLR |
| OTC | 300461 | ornithine transcarbamylase deficiency | XLR |
| OXCT1 | 601424 | Succinyl CoA:3-oxoacid CoA transferase deficiency | AR |
| PAH | 612349 | phenylketonuria | AR |
| PANK2 | 606157 | neurodegeneration with brain iron accumulation type 1; HARP syndrome | AR |
| PAX4 | 167413 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Maturity-onset diabetes of the young, type IX | AD, AR |
| PC | 608786 | pyruvate carboxylase deficiency | AR |
| PCCA | 232000 | propionic acidemia | AR |
| PCCB | 232050 | propionic acidemia | AR |
| PCK1 | 614168 | Phosphoenolpyruvate carboxykinase-1, cytosolic, deficiency | AR |
| PCSK9 | 607786 | hypercholesterolemia-3 | AD |
| PDHA1 | 300502 | Pyruvate dehydrogenase E1-alpha deficiency | XLD |
| PDHB | 179060 | Pyruvate dehydrogenase E1-beta deficiency | |
| PDHX | 608769 | Lacticacidemia due to PDX1 deficiency | AR |
| PDP1 | 605993 | Pyruvate dehydrogenase phosphatase deficiency | AR |
| PDSS1 | 607429 | Coenzyme Q10 deficiency, primary, 2 | AR |
| PDSS2 | 610564 | Coenzyme Q10 deficiency, primary, 3 | AR |
| PDX1 | 600733 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Pancreatic Agenesis, Congenital; MODY type 4 | AD, AR |
| PEPD | 613230 | Prolidase deficiency | AR |
| PET100 | 614770 | Mitochondrial complex IV deficiency | AR, M |
| PEX1 | 602136 | Peroxisome biogenesis disorder type 1A (Zellweger); Heimler syndrome type 1; peroxisome biogenesis disorder type 1B | AR |
| PEX10 | 602859 | peroxisome biogenesis disorder 6A (Zellweger); peroxisome biogenesis disorder 6B | AR |
| PEX11B | 603867 | peroxisome biogenesis disorder 14B (Zellweger) | AR |
| PEX12 | 601758 | peroxisome biogenesis disorder type 3B; peroxisome biogenesis disorder type 3A (Zellweger) | AR |
| PEX13 | 601789 | peroxisome biogenesis disorder 11A (Zellweger); peroxisome biogenesis disorder 11B | AR |
| PEX14 | 601791 | peroxisome biogenesis disorder 13A (Zellweger) | AR |
| PEX16 | 603360 | peroxisome biogenesis disorder 8A (Zellweger); Peroxisome biogenesis disorder 8B | AR |
| PEX19 | 600279 | peroxisome biogenesis disorder 12A (Zellweger) | AR |
| PEX2 | 170993 | peroxisome biogenesis disorder type 5A (Zellweger); peroxisome biogenesis disorder type 5B | AR |
| PEX26 | 608666 | peroxisome biogenesis disorder type 7A (Zellweger); peroxisome biogenesis disorder 7B | AR |
| PEX3 | 603164 | peroxisome biogenesis disorder 10A (Zellweger) | AR |
| PEX5 | 600414 | peroxisome biogenesis disorder 2B (Zellweger); peroxisome biogenesis disorder 2A (Zellweger); Rhizomelic chondrodysplasia punctata, type 5 | AR |
| PEX6 | 601498 | peroxisome biogenesis disorder type 4A (Zellweger); peroxisome biogenesis disorder type 4B; Heimler syndrome type 2 | AD, AR |
| PEX7 | 601757 | Rhizomelic chondrodysplasia punctata type 1; peroxisome biogenesis disorder type 9B (Zellweger) | AR |
| PFKM | 610681 | Glycogen storage disease type VII | AR |
| PGAM2 | 612931 | Glycogen storage disease X | AR |
| PGK1 | 311800 | Phosphoglycerate kinase 1 deficiency | XLR |
| PGM1 | 171900 | congenital disorder of glycosylation type 1t | AR |
| PHKA1 | 311870 | Muscle glycogenosis | XLR |
| PHKA2 | 300798 | glycogen storage disease type IX | XLR |
| PHKB | 172490 | Glycogen storage disease IXb; Phosphorylase kinase deficiency of liver and muscle | AR |
| PHKG2 | 172471 | Glycogen storage disease IXc | AR |
| PHYH | 602026 | Refsum disease | AR |
| PIK3R1 | 171833 | SHORT syndrome; Immunodeficiency 36 | AD, AR |
| PKLR | 609712 | pyruvate kinase deficiency | AD, AR |
| PLA2G6 | 603604 | infantile neuroaxonal dystrophy; neurodegeneration with brain iron accumulation 2B; Parkinson disease 14 | AR |
| PLCG2 | 600220 | Familial cold autoinflammatory syndrome 3 | AD |
| PLIN1 | 170290 | Lipodystrophy, familial partial, type 4 | AD |
| PLP1 | 300401 | Pelizaeus-Merzbacher disease; spastic paraplegia 2 | XLR |
| PMM2 | 601785 | congenital disorder of glycosylation type 1a | AR |
| PNPO | 603287 | Pyridoxamine 5'-phosphate oxidase deficiency | AR |
| PNPT1 | 610316 | Combined oxidative phosphorylation deficiency 13; Deafness, autosomal recessive 70 | AR |
| POLG | 174763 | progressive external ophthalmoplegia; mitochondrial DNA depletion syndrome type 4A; autosomal recessive progressive external ophthalmoplegia; sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; mitochondrial DNA depletion syndrome type 4B | AD, AR |
| POLR3A | 614258 | hypomyelinating leukodystrophy-7 | AR |
| POLR3B | 614366 | hypomyelinating leukodystrophy-8 | AR |
| POR | 124015 | Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis; Disordered Steroidogenesis Due To Cytochrome P450 Oxidoreductase Deficiency | AR |
| PPARG | 601487 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; OBESITY; Lipodystrophy, familial partial, type 3 | AD, AR |
| PPOX | 600923 | variegate porphyria | AD |
| PPT1 | 600722 | neuronal ceroid lipofuscinosis type 1 | AR |
| PRF1 | 170280 | familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin; Aplastic Anemia | AR |
| PRICKLE1 | 608500 | Epilepsy, progressive myoclonic 1B | AR |
| PRKAG2 | 602743 | Wolff-Parkinson-White syndrome; fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease; familial hypertrophic cardiomyopathy 6 | AD |
| PRKCD | 176977 | Autoimmune lymphoproliferative syndrome, type III | AR |
| PRODH | 606810 | Hyperprolinemia, type I; susceptibility to Schizophrenia, 4 | AD, AR |
| PSAP | 176801 | metachromatic leukodystrophy due to SAP-b deficiency; atypical Gaucher disease; Combined SAP deficiency; atypical Krabbe disease | AR |
| PSEN1 | 104311 | Pick disease; Dementia, frontotemporal; early-onset familial Alzheimer disease-3; dilated cardiomyopathy-1U; Acne inversa, familial, 3 | AD |
| PTF1A | 607194 | Pancreatic Agenesis 2 | AR |
| PTS | 612719 | Hyperphenylalaninemia, BH4-deficient, A | AR |
| PYCR2 | 616406 | hypomyelinating leukodystrophy-10 | AR |
| PYGL | 613741 | glycogen storage disease type 6 | AR |
| PYGM | 608455 | glycogen storage disease type 5 | AR |
| QDPR | 612676 | Hyperphenylalaninemia, BH4-deficient, C | AR |
| RAB27A | 603868 | Griscelli syndrome, type 2 | AR |
| RAI1 | 607642 | Smith-Magenis syndrome | AD |
| RARS1 | 107820 | hypomyelinating leukodystrophy-9 | AR |
| RARS2 | 611524 | pontocerebellar hypoplasia type 6 | AR |
| RBCK1 | 610924 | Polyglucosan body myopathy 1 with or without immunodeficiency | AR |
| RFT1 | 611908 | congenital disorder of glycosylation type 1n | AR |
| RFX6 | 612659 | Mitchell-Riley syndrome | AR |
| RNASEH2A | 606034 | Aicardi-Goutieres syndrome type 4 | AR |
| RNASEH2B | 610326 | Aicardi-Goutieres syndrome type 2 | AR |
| RNASEH2C | 610330 | Aicardi-Goutieres syndrome 3 | AR |
| RNASET2 | 612944 | Leukoencephalopathy, cystic, without megalencephaly | AR |
| RPIA | 180430 | AR | |
| RRM2B | 604712 | mitochondrial DNA depletion syndrome 8A; progressive external ophthalmoplegia with mitochondrial DNA deletions 5 | AD, AR |
| SAMHD1 | 606754 | Aicardi-Goutieres syndrome type 5; Chilblain lupus type 2 | AD, AR |
| SCARB2 | 602257 | Epilepsy, progressive myoclonic 4, with or without renal failure | AR |
| SCO1 | 603644 | Mitochondrial complex IV deficiency | AR, M |
| SCO2 | 604272 | Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1; Myopia 6 | AD, AR |
| SDHA | 600857 | mitochondrial complex II deficiency; Leigh syndrome; dilated cardiomyopathy-1GG; paragangliomas type 5 | AD, AR, M |
| SDHAF1 | 612848 | mitochondrial complex II deficiency | AR |
| SDHB | 185470 | paragangliomas type 4; pheochromocytoma; gastrointestinal stromal tumor; paraganglioma and gastric stromal sarcoma | AD |
| SDHD | 602690 | paragangliomas 1; pheochromocytoma; mitochondrial complex II deficiency; paraganglioma and gastric stromal sarcoma | AD, AR |
| SERAC1 | 614725 | 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL syndrome). | AR |
| SERPINI1 | 602445 | Encephalopathy, familial, with neuroserpin inclusion bodies | AD |
| SGSH | 605270 | mucopolysaccharidosis type IIIA | AR |
| SLC16A1 | 600682 | Monocarboxylate transporter 1 deficiency | AD, AR |
| SLC16A2 | 300095 | Allan-Herndon-Dudley syndrome | XL |
| SLC17A5 | 604322 | infantile sialic acid storage disorder; Salla disease | AR |
| SLC19A3 | 606152 | biotin-thiamine-responsive basal ganglia disease | AR |
| SLC22A5 | 603377 | systemic primary carnitine deficiency | AR |
| SLC25A1 | 190315 | Combined D-2- and L-2-hydroxyglutaric aciduria | AR |
| SLC25A12 | 603667 | Epileptic encephalopathy, early infantile, 39 | AR |
| SLC25A13 | 603859 | Citrullinemia, Type Ii, Adult-Onset; Citrullinemia, type II, neonatal-onset | AR |
| SLC25A15 | 603861 | Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome | AR |
| SLC25A20 | 613698 | Carnitine-acylcarnitine translocase deficiency | AR |
| SLC25A4 | 103220 | Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Dominant, 2; mitochondrial DNA depletion syndrome 12; mitochondrial DNA depletion syndrome type 12A | AD, AR |
| SLC2A1 | 138140 | Dystonia-9; GLUT1 deficiency syndrome; dystonia 18; Epilepsy, idiopathic generalized, suscpetibility to, 12 | AD, AR |
| SLC2A2 | 138160 | noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Fanconi-Bickel syndrome | AD, AR |
| SLC35A1 | 605634 | Congenital disorder of glycosylation, type IIf | AR |
| SLC35A2 | 314375 | congenital disorder of glycosylation type 2m | XLD |
| SLC35C1 | 605881 | Congenital disorder of glycosylation, type IIc | AR |
| SLC3A1 | 104614 | cystinuria | AD, AR |
| SLC40A1 | 604653 | Hemochromatosis, type 4 | AD |
| SLC4A1 | 109270 | Autosomal dominant distal renal tubular acidosis; resistance to malaria; Renal tubular acidosis, distal, with hemolytic anemia; Spherocytosis, type 4 | AD, AR |
| SLC6A8 | 300036 | Cerebral creatine deficiency syndrome type 1 | XLR |
| SLC6A9 | 601019 | Glycine encephalopathy with normal serum glycine | AR |
| SLC7A7 | 603593 | Lysinuric protein intolerance | AR |
| SLC7A9 | 604144 | cystinuria | AD, AR |
| SLCO1B1 | 604843 | Hyperbilirubinemia, Rotor type, digenic | DiR |
| SLCO1B3 | 605495 | Hyperbilirubinemia, Rotor type, digenic | DiR |
| SMPD1 | 607608 | Niemann-Pick disease type A; Niemann-Pick disease type A/B | AR |
| SNTA1 | 601017 | long QT syndrome 12 | AD |
| SOX10 | 602229 | PCWH syndrome; Waardenburg syndrome type 2E; Waardenburg syndrome, type 4C | AD |
| SPART | 607111 | spastic paraplegia 20 | AR |
| SPG11 | 610844 | Amyotrophic lateral sclerosis 5, juvenile; spastic paraplegia type 11; Charcot-Marie-Tooth disease, axonal, type 2X | AR |
| SPG7 | 602783 | spastic paraplegia 7 | AD, AR |
| SPTA1 | 182860 | Elliptocytosis type 2; Pyropoikilocytosis; Spherocytosis, type 3 | AD, AR |
| SPTB | 182870 | Spherocytosis, type 2; Elliptocytosis 3 | AD |
| SRD5A3 | 611715 | congenital disorder of glycosylation type 1q; Kahrizi syndrome | AR |
| SSR4 | 300090 | congenital disorder of glycosylation type 1y | XLR |
| STAT1 | 600555 | Autosomal recessive Immunodeficiency 31B, mycobacterial and viral infections; Immunodeficiency 31C, autosomal dominant | AD, AR |
| STT3A | 601134 | congenital disorder of glycosylation type 1w | AR |
| STT3B | 608605 | Congenital disorder of glycosylation, type Ix | AR |
| STX11 | 605014 | Hemophagocytic lymphohistiocytosis, familial, 4 | AR |
| STXBP2 | 601717 | Hemophagocytic lymphohistiocytosis, familial, 5 | |
| SUCLA2 | 603921 | mitochondrial DNA depletion syndrome 5 | AR |
| SUCLG1 | 611224 | mitochondrial DNA depletion syndrome 9 | AR |
| SUGCT | 609187 | AR | |
| SUMF1 | 607939 | multiple sulfatase deficiency | AR |
| SUOX | 606887 | Sulfite oxidase deficiency | AR |
| SURF1 | 185620 | Leigh syndrome | AR, M |
| SYNE1 | 608441 | autosomal recessive spinocerebellar ataxia 8; Emery-Dreifuss muscular dystrophy 4 | AD, AR |
| TACO1 | 612958 | Mitochondrial complex IV deficiency | AR, M |
| TAT | 613018 | Tyrosinemia type II | AR |
| TAZ | 300394 | Barth syndrome | XLR |
| TBC1D24 | 613577 | DOOR syndrome; Myoclonic epilepsy, infantile, familial; Rolandic epilepsy with proxysmal exercise-induced dystonia and writer's cramp; deafness type 86; Epileptic encephalopathy, early infantile, 16; deafness type 65 | AD, AR |
| TCF4 | 602272 | Pitt-Hopkins syndrome | AD |
| TCN2 | 613441 | Transcobalamin II deficiency | AR |
| TFR2 | 604720 | hemochromatosis type 3 | AR |
| TGFB1 | 190180 | Camurati-Engelmann disease; cystic fibrosis | AD, AR |
| TINF2 | 604319 | Revesz syndrome; Dyskeratosis congenita, autosomal dominant 3 | AD |
| TK2 | 188250 | mitochondrial DNA depletion syndrome 2 | AR |
| TMEM165 | 614726 | Congenital disorder of glycosylation, type IIk | AR |
| TMEM70 | 612418 | Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 | AR |
| TPK1 | 606370 | Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) | AR |
| TPP1 | 607998 | neuronal ceroid lipofuscinosis type 2; autosomal recessive spinocerebellar ataxia type 7 | AR |
| TREM2 | 605086 | polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy type 2 | AD |
| TREX1 | 606609 | systemic lupus erythematosus; retinal vasculopathy with cerebral leukodystrophy; Aicardi-Goutieres syndrome type 1; chilblain lupus type 1 | AD, AR |
| TRPV4 | 605427 | Brachyolmia type 3; Metatropic dysplasia; Spondylometaphyseal dysplasia, Kozlowski type; Hereditary motor and sensory neuropathy, type IIc | AD |
| TSFM | 604723 | Combined oxidative phosphorylation deficiency 3 | AR |
| TTC19 | 613814 | nuclear mitochondrial complex III deficiency type 2 | AR |
| TUBB4A | 602662 | dystonia 4; hypomyelinating leukodystrophy-6 | AD |
| TUFM | 602389 | Combined oxidative phosphorylation deficiency 4 | AR |
| TUSC3 | 601385 | MENTAL RETARDATION, AUTOSOMAL RECESSIVE 7 | AR |
| TWNK | 606075 | Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Progressive external ophthalmoplegia, autosomal dominant, 3 | AD, AR |
| TYMP | 131222 | mitochondrial DNA depletion syndrome 1 | AR |
| TYROBP | 604142 | polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy type 1 | AR |
| UCP2 | 601693 | ||
| UGT1A1 | 191740 | Gilbert syndrome; Crigler-Najjar syndrome type I; familial transient neonatal hyperbilirubinemia; serum level of Bilirubin, QTL1; Crigler-Najjar syndrome type II | AR |
| UMPS | 613891 | Orotic aciduria | AR |
| UNC13D | 608897 | familial hemophagocytic lymphohistiocytosis 3 | AR |
| UQCRQ | 612080 | Mitochondrial complex III deficiency, nuclear type 4 | AR |
| UROD | 613521 | hepatoerythropoietic porphyria | AD, AR |
| UROS | 606938 | Porphyria, congenital erythropoietic | AR |
| WDR45 | 300526 | neurodegeneration with brain iron accumulation 5 | XLD |
| WFS1 | 606201 | congenital nuclear cataract type 41; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Wolfram syndrome; Deafness, autosomal dominant 6/14/38; Wolfram-like syndrome | AD, AR |
| ZFP57 | 612192 | Diabetes mellitus, transient neonatal, 1 | AD |
| ZFYVE26 | 612012 | spastic paraplegia type 15 | AR |
Therapy for MMA includes restoration of the volume status and acid-base balance and reduction or elimination of protein intake, and frequent monitoring of serum electrolytes and ammonia, venous or arterial blood gases, and urine output. Management includes a high-calorie diet low in propionic amino acid precursors; hydroxocobalamin intramuscular injections; carnitine supplementation; and antibiotics for treatment of infections. Other therapies include N-carbamylglutamate for the treatment of acute hyperammonemia episodes; liver, kidney, or combined liver and kidney transplantation; and antioxidants for the treatment of optic nerve atrophy.
CENTOGENE offers sequencing and deletion/duplication analysis for the genes in the Methylmalonic acidemia panel (advanced) (ABCD4, ACSF3, CD320, LMBRD1, MCEE, MLYCD, MMAA, MMAB, MMACHC, MMADHC, MTR, MTRR, MUT, SUCLA2, SUCLG1).
Differential diagnosis
The differential diagnosis of Methylmalonic acidemia-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Atypical methylmalonic acidemia
- "Benign" methylmalonic academia
- Combined malonic and methylmalonic aciduria (CMAMMA) caused by ACSF3 deficiency
- Methylmalonate semialdehyde dehydrogenase deficiency (MMSDH)
- Transcobalamin receptor defect (TCblR/CD320)
- Combined methylmalonic acidemia and hyperhomocysteinemia/homocystinuria
- Vitamin B12 deficiency
- Mitochondrial encephalomyopathy with elevated methylmalonic acid.
Testing strategy
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for methylmalonic acidemia using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Methylmalonic acidemia panel (advanced). Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no mutation is identified after analysis of the Methylmalonic acidemia panel (advanced), we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
Referral reasons
The following individuals are candidates for methylmalonic acidemia testing:
- Individuals with a family history of Methylmalonic acidemia and presentation of the most common symptoms
- Individuals without a positive family history of Methylmalonic acidemia, but with symptoms resembling the disease
- Individuals with a negative but suspected family history of Methylmalonic acidemia, in order to perform proper genetic counseling.
Test utility
Sequencing, deletion/duplication of the Methylmalonic acidemia panel genes should be performed in all individuals suspected of having Methylmalonic acidemia-related disorders. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the Methylmalonic acidemia and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.