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  3. NGS Panel – Genetic Testing for Methylmalonic Acidemia

Methylmalonic Acidemia

September 05, 2017

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 CentoMD® exclusive variant numbers (++)
AARS2 612035 Combined oxidative phosphorylation deficiency 8; Leukoencephalopathy, progressive, with ovarian failure AR 9
ABCA1 600046 Tangier disease; HDL deficiency, type 2 AR 19
ABCB4 171060 gallbladder disease type 1; progressive familial intrahepatic cholestasis type 3; Cholestasis, intrahepatic, of pregnancy, 3 AD, AR 31
ABCC2 601107 Dubin-Johnson syndrome AR 19
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 33
ABCD1 300371 adrenoleukodystrophy XLR 42
ABCD3 170995 congenital bile acid synthesis defect-5 AR 0
ABCD4 603214 Methylmalonic aciduria and homocystinuria, cblJ type AR 10
ACAD8 604773 AR 0
ACAD9 611103 Acyl-Coa Dehydrogenase Family, Member 9, Deficiency Of AR 22
ACADM 607008 medium chain acyl-CoA dehydrogenase deficiency AR 19
ACADS 606885 short-chain acyl-CoA dehydrogenase deficiency AR 7
ACADSB 600301 2-methylbutyrylglycinuria AR 0
ACADVL 609575 very long chain acyl-CoA dehydrogenase deficiency AR 27
ACAT1 607809 alpha-methylacetoacetic aciduria AR 11
ACOX1 609751 Peroxisomal acyl-CoA oxidase deficiency AR 7
ACSF3 614245 Combined malonic and methylmalonic aciduria 16
ACY1 104620 Aminoacylase 1 deficiency AR 7
ADA 608958 Adenosine deaminase deficiency AR 6
ADAMTSL2 612277 Geleophysic dysplasia 1 AR 7
ADAR 146920 Dyschromatosis symmetrica hereditaria; Aicardi-Goutieres syndrome type 6 AD, AR 17
ADGRG1 604110 bilateral frontoparietal polymicrogyria; bilateral perisylvian polymicrogyria AR 11
ADK 102750 Hypermethioninemia due to adenosine kinase deficiency AR 2
ADSL 608222 Adenylosuccinase deficiency AR 6
AFG3L2 604581 spinocerebellar ataxia 28; spastic ataxia 5 AD, AR 23
AGA 613228 Aspartylglucosaminuria AR 5
AGL 610860 glycogen storage disease type III AR 86
AGPAT2 603100 Lipodystrophy, congenital generalized, type 1 AR 9
AGPS 603051 rhizomelic chondrodysplasia punctata type 3 AR 7
AGXT 604285 primary hyperoxaluria type 1 AR 7
AHCY 180960 Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase AR 1
AIFM1 300169 Deafness, X-linked 5; Combined oxidative phosphorylation deficiency 6; Cowchock syndrome XLR 6
AIMP1 603605 hypomyelinating leukodystrophy-3 AR 7
AKT2 164731 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Hypoinsulinemic hypoglycemia with hemihypertrophy AD 2
ALAD 125270 Acute hepatic porphyria AR 4
ALAS2 301300 X-linked sideroblastic anemia; Protoporphyria, erythropoietic, X-linked XL, XLR 4
ALDH3A2 609523 Sjogren-Larsson syndrome AR 6
ALDH4A1 606811 hyperprolinemia, type II AR 1
ALDH5A1 610045 Succinic semialdehyde dehydrogenase deficiency AR 5
ALDH7A1 107323 pyridoxine-dependent epilepsy AR 22
ALDOA 103850 Glycogen storage disease XII AR 8
ALDOB 612724 hereditary fructose intolerance AR 7
ALG1 605907 congenital disorder of glycosylation type 1k AR 5
ALG11 613666 congenital disorder of glycosylation type 1p AR 6
ALG12 607144 congenital disorder of glycosylation type 1g AR 1
ALG13 300776 congenital disorder of glycosylation type 1s XLD 6
ALG2 607905 congenital disorder of glycosylation type 1i AR 2
ALG3 608750 congenital disorder of glycosylation type 1d AR 4
ALG6 604566 congenital disorder of glycosylation type 1c AR 1
ALG8 608103 congenital disorder of glycosylation type 1h AD, AR 2
ALG9 606941 Gillessen-Kaesbach-Nishimura syndrome; congenital disorder of glycosylation type 1l AR 0
ALPL 171760 adult hypophosphatasia; infantile hypophosphatasia; childhood-onset hypophosphatasia AD, AR 40
AMN 605799 AR 10
AMT 238310 glycine encephalopathy AR 8
ANK1 612641 Spherocytosis, type 1 AD, AR 9
ANTXR2 608041 Hyaline fibromatosis syndrome AR 8
AP3B1 603401 Hermansky-Pudlak syndrome type 2 AR 18
AP4B1 607245 spastic paraplegia 47 AR 8
AP4E1 607244 spastic paraplegia 51 AD, AR 7
AP4M1 602296 autosomal recessive spastic paraplegia type 50 AR 11
AP4S1 607243 spastic paraplegia 52 AR 0
APOA5 606368 HYPERLIPOPROTEINEMIA, TYPE V; Hypertriglyceridemia, susceptibility to AD 4
APOB 107730 Hypercholesterolemia, Type B; Hypobetalipoproteinemia AD, AR 64
APOC2 608083 Apolipoprotein C-Ii Deficiency AR 5
APOE 107741 Alzheimer Disease 2; Sea-blue histiocyte disease; Macular Degeneration, Age-Related, 1; early-onset familial Alzheimer disease-3; Lipoprotein glomerulopathy AD, AR 10
APP 104760 Alzheimer Disease; Cerebral Amyloid Angiopathy, App-Related AD 37
APTX 606350 Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia AR 30
ARG1 608313 Argininemia AR 5
ARSA 607574 metachromatic leukodystrophy AR 76
ARSB 611542 mucopolysaccharidosis type VI AR 79
ASAH1 613468 Spinal muscular atrophy with progressive myoclonic epilepsy; Farber lipogranulomatosis AR 54
ASL 608310 argininosuccinic aciduria AR 18
ASPA 608034 Canavan disease AR 15
ASS1 603470 citrullinemia AR 22
ATM 607585 familial breast-ovarian cancer type 2; ataxia-telangiectasia AD, AR 82
ATP13A2 610513 Kufor-Rakeb syndrome; spastic paraplegia type 78 AR 30
ATP6V0A2 611716 autosomal recessive cutis laxa type IIA; Wrinkly skin syndrome AR 1
ATP7A 300011 X-linked distal spinal muscular atrophy type 3; Occipital horn syndrome; Menkes disease XLR 30
ATP7B 606882 Wilson disease AR 42
ATPAF2 608918 Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1 AR 4
AUH 600529 3-methylglutaconic aciduria, type I AR 8
B3GALNT2 610194 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A11 AR 5
B4GALT1 137060 congenital disorder of glycosylation type 2d AR 2
BCAP31 300398 Deafness, dystonia, and cerebral hypomyelination; ddch contiguous abcd1/dxs1375e deletion syndrome, included; cadds, included XLR 3
BCKDHA 608348 maple syrup urine disease type Ia; maple syrup urine disease type Ib; maple syrup urine disease type II AR 29
BCKDHB 248611 maple syrup urine disease type Ia; maple syrup urine disease type Ib; maple syrup urine disease type II AR 20
BCS1L 603647 Mitochondrial complex III deficiency, nuclear type 1; Leigh syndrome; Bjornstad syndrome; GRACILE syndrome AR, M 6
BEST1 607854 vitelliform macular dystrophy-2; vitreoretinochoroidopathy; Bestrophinopathy, autosomal recessive; Retinitis pigmentosa 50 AD 29
BLK 191305 MODY type 11 AD 15
BOLA3 613183 Multiple mitochondrial dysfunctions syndrome 2 AR 0
BRAT1 614506 Rigidity and multifocal seizure syndrome, lethal neonatal; neurodevelopmental disorder with cerebellar atrophy and with or without seizures AR 6
BSCL2 606158 Lipodystrophy, congenital generalized, type 2; spastic paraplegia 17; Neuropathy, distal hereditary motor, type V; Encephalopathy, progressive, with or without lipodystrophy AD, AR 16
BTD 609019 biotinidase deficiency AR 17
C12orf65 613541 Combined oxidative phosphorylation deficiency 7 AR 2
C19orf12 614297 neurodegeneration with brain iron accumulation 4; spastic paraplegia 43 AD, AR 7
CA5A 114761 Hyperammonemia due to carbonic anhydrase VA deficiency AR 4
CASP10 601762 Autoimmune lymphoproliferative syndrome, type II; Lymphoma, non-Hodgkin; Gastric Cancer AD 4
CASP8 601763 familial breast-ovarian cancer type 2; Hepatocellular Carcinoma; Lung Cancer AD, AR 0
CAV1 601047 AD, AR 0
CAVIN1 603198 Lipodystrophy, congenital generalized, type 4 AR 2
CBLIF 609342 Intrinsic factor deficiency AR 3
CBS 613381 homocystinuria with or without response to pyridoxine AR 29
CD320 606475 Methylmalonic aciduria due to transcobalamin receptor defect 3
CEL 114840 MODY type 8 AD 38
CERS1 606919 Progressive myoclonic epilepsy-8 AR 1
CIDEC 612120 Lipodystrophy, familial partial, type 5 AR 0
CISD2 611507 Wolfram syndrome 2 AR 14
CLCN2 600570 Epilepsy, Idiopathic Generalized, Susceptibility To, 11; Leukoencephalopathy with ataxia AD, AR 14
CLN3 607042 neuronal ceroid lipofuscinosis type 3 AR 16
CLN5 608102 neuronal ceroid lipofuscinosis type 5 AR 13
CLN6 606725 adulte onset neuronal ceroid lipofuscinosis, Kufs type; neuronal ceroid lipofuscinosis type 6 AR 38
CLN8 607837 neuronal ceroid lipofuscinosis type 8; neuronal ceroid lipofuscinosistype 8, Northern epilepsy variant AR 6
CLPB 616254 3-methylglutaconic aciduria type VII with cataracts, neurologic involvement and neutropenia AR 2
CLPP 601119 Perrault syndrome 3 AR 3
COA8 616003 Mitochondrial complex IV deficiency AR, M 1
COASY 609855 Neurodegeneration with brain iron accumulation 6; Pontocerebellar hypoplasia type 12 AR 1
COG1 606973 Congenital disorder of glycosylation, type IIg AR 1
COG4 606976 congenital disorder of glycosylation type 2j; Saul-Wilson syndrome AD, AR 4
COG5 606821 Congenital disorder of glycosylation, type IIi AR 0
COG6 606977 congenital disorder of glycosylation type 2l; Shaheen syndrome AR 4
COG7 606978 Congenital disorder of glycosylation, type IIe AR 3
COG8 606979 congenital disorder of glycosylation type 2h 1
COL11A2 120290 Stickler syndrome, type III; Otospondylomegaepiphyseal dysplasia; Deafness, autosomal dominant 13; Deafness, autosomal recessive 53; Fibrochondrogenesis 2 AD, AR 38
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 38
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 71
COL4A2 120090 Brain small vessel disease type 2; Hemorrhage, intracerebral, susceptibility to AD 18
COQ2 609825 Multiple system atrophy, susceptibility to; Coenzyme Q10 deficiency, primary, 1 AD, AR 18
COQ8A 606980 primary Coenzyme Q10 deficiency type 4 - COQ10D4 AR 32
COQ9 612837 Coenzyme Q10 deficiency, primary, 5 AR 12
COX10 602125 Mitochondrial complex IV deficiency; Leigh syndrome AR, M 16
COX15 603646 Leigh syndrome; Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 AR, M 4
COX20 614698 Mitochondrial complex IV deficiency AR, M 1
COX6B1 124089 Mitochondrial complex IV deficiency AR, M 0
CP 117700 aceruloplasminemia AR 17
CPOX 612732 Coproporphyria, hereditary AD, AR 11
CPS1 608307 carbamoyl-phosphate synthetase 1 deficiency AR 36
CPT1A 600528 hepatic CPT deficiency type IA AR 14
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 13
CSF1R 164770 hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia AD, AR 30
CTC1 613129 Cerebroretinal microangiopathy with calcifications and cysts AR 3
CTH 607657 Cystathioninuria AR 0
CTLA4 123890 systemic lupus erythematosus; Autoimmune lymphoproliferative syndrome, type V AD 2
CTNS 606272 ocular nonnephropathic cystinosis; cystinosis; late-onset juvenile or adolescent nephropathic cystinosis AR 12
CTSA 613111 galactosialidosis AR 17
CTSC 602365 Papillon-Lefevre syndrome AR 8
CTSD 116840 neuronal ceroid lipofuscinosis type 10 AR 8
CTSF 603539 neuronal ceroid lipofuscinosis type 13 AR 3
CTSK 601105 pycnodysostosis AR 12
CUBN 602997 megaloblastic anemia 1 AR 46
CYP11B1 610613 Glucocorticoid-Remediable Aldosteronism; Adrenal Hyperplasia, Congenital, Due To Steroid 11-Beta-Hydroxylase Deficiency AD, AR 7
CYP17A1 609300 congenital adrenal hyperplasia due to 17-Alpha-Hydroxylase deficiency AR 7
CYP19A1 107910 Aromatase excess syndrome; Aromatase deficiency AD 10
CYP21A2 613815 congenital adrenal hyperplasia type 1 AR 44
CYP27A1 606530 cerebrotendinous xanthomatosis AR 6
CYP2U1 610670 spastic paraplegia 56 AR 21
CYP7B1 603711 spastic paraplegia 5A AR 17
D2HGDH 609186 D-2-Hydroxyglutaric Aciduria 1 AR 2
DAG1 128239 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type C9 AR 6
DARS2 610956 leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation AR 14
DBT 248610 maple syrup urine disease type Ia; maple syrup urine disease type Ib; maple syrup urine disease type II AR 23
DCAF17 612515 Woodhouse-Sakati syndrome AR 6
DDC 107930 Aromatic L-amino acid decarboxylase deficiency AR 6
DDOST 602202 Congenital disorder of glycosylation, type Ir AR 1
DGUOK 601465 mitochondrial DNA depletion syndrome 3 AR 8
DHCR7 602858 Smith-Lemli-Opitz syndrome AR 9
DHDDS 608172 retinitis pigmentosa type 59; Developmental delay and seizures with or without movement abnormalities AD, AR 2
DIABLO 605219 Deafness, autosomal dominant 64 AD 1
DKC1 300126 X-linked dyskeratosis congenita XLR 3
DLAT 608770 Pyruvate dehydrogenase E2 deficiency AR 10
DLD 238331 dihydrolipoamide dehydrogenase deficiency AR 11
DNAJC5 611203 neuronal ceroid lipofuscinosis type 4, Parry type AD 2
DNM1L 603850 Encephalopahty, lethal, due to defective mitochondrial peroxisomal fission AD, AR 8
DOLK 610746 congenital disorder of glycosylation type 1m AR 2
DPM1 603503 Congenital disorder of glycosylation, type Ie AR 1
DPM2 603564 Congenital disorder of glycosylation, type Iu AR 0
DPM3 605951 congenital disorder of glycosylation, type Io AR 1
DPYD 612779 Dihydropyrimidine dehydrogenase deficiency AR 8
DYM 607461 Dyggve-Melchior-Clausen disease AR 5
EARS2 612799 Combined oxidative phosphorylation deficiency 12 AR 4
ECHS1 602292 mitochondrial short-chain enoyl-CoA hydratase 1 deficiency AR 3
EIF2AK3 604032 Wolcott-Rallison syndrome AR 2
EIF2B1 606686 leukoencephaly with vanishing white matter AR 4
EIF2B2 606454 leukoencephaly with vanishing white matter AR 12
EIF2B3 606273 leukoencephaly with vanishing white matter AR 11
EIF2B4 606687 leukoencephaly with vanishing white matter AR 11
EIF2B5 603945 leukoencephaly with vanishing white matter AR 7
ENO3 131370 Glycogen storage disease XIII AR 13
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 8
EPB42 177070 Spherocytosis, type 5 0
EPHX2 132811 familial hypercholesterolemia AD 4
EPM2A 607566 Epilepsy, progressive myoclonic 2A (Lafora); Epilepsy, progressive myoclonic 2B (Lafora) AR 5
ERCC6 609413 Cockayne syndrome, type B; Lung Cancer; Cerebrooculofacioskeletal syndrome 1 AD, AR 12
ETFA 608053 multiple acyl-CoA dehydrogenase deficiency AR 13
ETFB 130410 multiple acyl-CoA dehydrogenase deficiency AR 11
ETFDH 231675 multiple acyl-CoA dehydrogenase deficiency AR 16
ETHE1 608451 ethylmalonic encephalopathy AR 6
F2 176930 thrombophilia due to thrombin defect; susceptibility to ischemic stroke; congenital prothrombin deficiency; susceptibility to recurrent pregnancy loss type 2 AD, AR 0
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 11
FA2H 611026 spastic paraplegia 35 AR 30
FADD 602457 recurrent infections with encephalopathy, hepatic dysfunction and cardiovasuclar malformations AR 1
FAH 613871 tyrosinemia type 1 AR 17
FAM126A 610531 hypomyelinating leukodystrophy-5 AR 11
FARS2 611592 Combined oxidative phosphorylation deficiency 14; spastic paraplegia type 77 AR 7
FAS 134637 Autoimmune lymphoproliferative syndrome AD 4
FASLG 134638 Lung Cancer; Autoimmune lymphoproliferative syndrome AD 1
FASTKD2 612322 AR 6
FBN1 134797 Marfan syndrome; stiff skin syndrome; Weill-Marchesani syndrome 2; geleophysic dysplasia 2; Marfan lipodystrophy syndrome AD 76
FBP1 611570 Fructose-1,6-bidphosphatase deficiency AR 14
FBXL4 605654 mitochondrial DNA depletion syndrome 13 AR 7
FECH 612386 Protoporphyria, erythropoietic, autosomal recessive AR 3
FGF23 605380 Hypophosphatemic rickets, autosomal dominant AD, AR 6
FH 136850 Leiomyomatosis and renal cell cancer; Fumarase deficiency AD, AR 2
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 13
FOLR1 136430 cerebral folate transport deficiency AR 5
FOXP3 300292 Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked XLR 5
FOXRED1 613622 AR 6
FTL 134790 Hyperferritinemia With Or Without Cataract; neurodegeneration with brain iron accumulation 3 AD, AR 6
FUCA1 612280 fucosidosis AR 24
G6PC 613742 glycogen storage disease type IA AR 16
G6PD 305900 glucose-6-phosphate dehydrogenase deficiency; resistance to malaria XLD 10
GAA 606800 Pompe disease AR 130
GALC 606890 Krabbe disease AR 89
GALE 606953 Galactose epimerase deficiency AR 5
GALK1 604313 galactokinase deficiency AR 6
GALNS 612222 mucopolysaccharidosis type IVA AR 178
GALT 606999 galactosemia AR 12
GAMT 601240 guanidinoacetate methyltransferase deficiency AR 11
GAN 605379 giant axonal neuropathy AR 9
GATA6 601656 Tetralogy of Fallot; Conotruncal Heart Malformations; Pancreatic agenesis and congenital heart defects; Atrioventricular septal defect 5; Atrial septal defect 9 AD 2
GATM 602360 Cerebral creatine deficiency syndrome 3 AD, AR 1
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 176
GBE1 607839 storage disease type 4; Polyglucosan body disease, adult form AR 40
GCDH 608801 glutaric academia type I AR 21
GCK 138079 MODY type 2; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Hyperinsulinemic hypoglycemia, familial, 3; permanent neonatal diabetes mellitus AD, AR 30
GCSH 238330 glycine encephalopathy AR 16
GFAP 137780 Alexander disease AD 24
GFER 600924 Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay 1
GFM1 606639 Combined oxidative phosphorylation deficiency 1 AR 10
GFM2 606544 AR 0
GFPT1 138292 congenital myasthenic syndrome with tubular aggregates type 1 AR 7
GHR 600946 familial hypercholesterolemia; Laron syndrome; Increased responsiveness to growth hormone AD, AR 11
GJA1 121014 Oculodentodigital dysplasia AD, AR 3
GJB1 304040 Charcot-Marie-Tooth disease type 1 XLD 13
GJC2 608803 Leukodystrophy, hypomyelinating, 2; spastic paraplegia 44 AD, AR 28
GK 300474 Glycerol kinase deficiency XLR 15
GLA 300644 Fabry disease; Fabry disease, atypical cardiac variant XL 630
GLB1 611458 GM1-gangliosidosis; GM1-gangliosidosis type II; GM1-gangliosidosis type III; mucopolysaccharidosis type IVB AR 93
GLDC 238300 glycine encephalopathy AR 64
GLIS3 610192 Diabetes mellitus, neonatal, with congenital hypothyroidism AR 6
GLRX5 609588 Anemia, sideroblastic, 3, pyridoxine-refractory AR 3
GLUD1 138130 familial hyperinsulinemic hypoglycemia-6 AD 5
GLUL 138290 Glutamine deficiency, congenital AR 4
GM2A 613109 GM2-gangliosidosis, AB variant AR 7
GMPPA 615495 Alacrima, achalasia, and mental retardation syndrome AR 2
GNE 603824 Sialuria; Nonaka myopathy AD, AR 6
GNMT 606628 AR 1
GNPAT 602744 rhizomelic chondrodysplasia punctata type 2 AR 6
GNPTAB 607840 mucolipidosis II alpha/beta; mucolipidosis III alpha/beta AR 37
GNPTG 607838 mucolipidosis III gamma AR 9
GNS 607664 mucopolysaccharidosis type IIID AR 17
GOSR2 604027 Epilepsy, progressive myoclonic 6 AR 0
GPC3 300037 Wilms tumor, type 1; Simpson-Golabi-Behmel syndrome, type 1 XLR 7
GRN 138945 frontotemporal lobar degeneration with ubiquitin-positive inclusions; neuronal ceroid lipofuscinosis type 11 AD, AR 16
GTPBP3 608536 Combined oxidative phosphorylation deficiency 23 AR 3
GUSB 611499 mucopolysaccharidosis type VII AR 29
GYG1 603942 Glycogen storage disease XV; Polyglucosan body myopathy 2 AR 11
GYS1 138570 Glycogen storage disease 0, muscle AR 8
GYS2 138571 Glycogen storage disease 0, liver AR 24
HADH 601609 3-hydroxyacyl-CoA dehydrogenase deficiency; familial hyperinsulinemic hypoglycemia type 4 AR 0
HADHA 600890 mitochondrial trifunctional protein deficiency; long-chain 3-hydroxyl-CoA dehydrogenase deficiency AR 11
HADHB 143450 mitochondrial trifunctional protein deficiency AR 13
HAMP 606464 Hemochromatosis, type 2B AR 0
HCFC1 300019 mental retardation 3 XLR 15
HEPACAM 611642 megalencephalic leukoencephalopathy with subcortical cysts type 2A; megalencephalic leukoencephalopathy with subcortical cysts type 2B, remitting, with or without mental retardation AD, AR 6
HEXA 606869 Tay-Sachs disease/ GM2-gangliosidosis AR 25
HEXB 606873 Sandhoff disease AR 37
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 11
HGD 607474 Alkaptonuria AR 5
HGSNAT 610453 mucopolysaccharidosis type IIIC; retinitis pigmentosa type 73 AR 40
HIBCH 610690 3-hydroxyisobutryl-CoA hydrolase deficiency AR 8
HJV 608374 hemochromatosis type 2A AR 4
HLCS 609018 Holocarboxylase synthetase deficiency AR 4
HMBS 609806 acute intermittent porphyria AD 19
HMGCL 613898 HMG-CoA lyase deficiency AR 10
HMGCS2 600234 HMG-CoA synthase-2 deficiency AR 4
HNF1A 142410 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Renal carcinoma, chromophobe, somatic; Diabetes mellitus, insulin-dependent-1; MODY type 3 AD, AR 20
HNF1B 189907 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 5; Renal carcinoma, chromophobe, somatic AD 14
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 11
HPD 609695 Tyrosinemia, type III AD, AR 0
HPRT1 308000 Lesch-Nyhan syndrome; Kelley-Seegmiller syndrome XLR 10
HRAS 190020 Bladder Cancer; Melanocytic nevus syndrome, congenital, somatic; Nevus, Epidermal; Schimmelpenning-Feuerstein-Mims Syndrome; Thyroid Carcinoma, Follicular; Costello syndrome AD 10
HSD17B10 300256 HSD10 mitochondrial disease XLD 7
HSD17B4 601860 Perrault syndrome type 1; D-bifunctional protein deficiency AR 27
HSD3B2 613890 3-beta-hydroxysteroid dehydrogenase 2 deficiency AR 4
HSPD1 118190 spastic paraplegia 13; hypomyelinating leukodystrophy-4 AD, AR 17
HTRA1 602194 Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 AD, AR 2
HYAL1 607071 Mucopolysaccharidosis type IX AR 3
IARS2 612801 Cataracts, Growth Hormone Deficiency, sensory neuropathy, sensorineural hearing loss, skeletal dysplasia AR 1
IBA57 615316 Multiple mitochondrial dysfunctions syndrome 3 AR 4
IDS 300823 mucopolysaccharidosis type II XLR 236
IDUA 252800 mucopolysaccharidosis type IH; mucopolysaccharidosis type 1; mucopolysaccharidosis type IS AR 77
IER3IP1 609382 Microcephaly, epilepsy, and diabetes syndrome AR 1
IFIH1 606951 Singleton-Merten syndrome type 1; Aicardi-Goutieres syndrome 7 AD 28
INS 176730 Diabetes Mellitus, Insulin-Dependent, 2; MODY type 10 AD, AR 5
INSR 147670 Donohue syndrome; Rabson-Mendenhall syndrome; Hyperinsulinemic hypoglycemia, familial, 5; Diabetes mellitus, insulin-resistant, with acanthosis nigricans AD, AR 34
ISCA2 615317 Multiple mitochondrial dysfunctions syndrome type 4 AR 6
ITK 186973 Lymphoproliferative syndrome 1 AR 0
IVD 607036 isovaleric acidemia AR 18
JAG1 601920 Alagille syndrome; Tetralogy of Fallot AD 43
JAM3 606871 Hemorrhagic destruction of the brain, subpendymal calcification, and cataracts AR 1
KCNC1 176258 Progressive myoclonic epilepsy 7 AD 3
KCNJ10 602208 autosomal recessive deafness type 4 with enlarged vestibular aqueduct; Seizures, Sensorineural Deafness, Ataxia, Mental Retardation, And Electrolyte Imbalance AR 7
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 7
KCNT1 608167 early infantile epileptic encephalopathy 14; nocturnal frontal lobe epilepsy 5 AD 52
KCTD7 611725 progressive myoclonic epilepsy type 3 with or without intracellular inclusions AR 7
KIF5A 602821 spastic paraplegia 10; Neonatal intractable myoclonus AD 28
KLF11 603301 MODY type 7 12
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 9
L2HGDH 609584 L-2-hydroxyglutaric aciduria AR 12
LAMA2 156225 congenital muscular dystrophy type 1A; limb-girdle Muscular dystrophy type 23 AR 44
LAMB1 150240 lissencephaly 5 AR 6
LAMP2 309060 Danon disease XLD 12
LARGE1 603590 congenital muscular dystrophy-dystroglycanopathy with mental retardation type B6; congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A6 AR 19
LDB3 605906 dilated cardiomyopathy-1C; Myopathy, myofibrillar, 4 AD 8
LDHA 150000 Glycogen storage disease XI AR 5
LDLR 606945 familial hypercholesterolemia AD 11
LDLRAP1 605747 Hypercholesterolemia, Autosomal Recessive AR 2
LIAS 607031 Pyruvate dehydrogenase lipoic acid synthetase deficiency AR 1
LIPA 613497 Wolman disease / cholesteryl ester storage disease AR 21
LIPE 151750 Lipodystrophy, familial partial, type 6 AR 0
LIPT1 610284 Lipoyltransferase 1 deficiency AR 1
LMBRD1 612625 Methylmalonic aciduria and homocystinuria, cblF type AR 5
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 20
LMNB1 150340 Leukodystrophy, adult-onset, autosomal dominant AD 18
LPIN1 605518 Myoglobinuria, acute recurrent, autosomal recessive AR 23
LPL 609708 familial combined hyperlipidemia; lipoprotein lipase deficiency AD, AR 14
LRPPRC 607544 Leigh syndrome, French-Canadian type AR 20
LYRM7 615831 Mitochondrial complex III deficiency nuclear type 8 AR 0
LYST 606897 Chediak-Higashi syndrome AR 30
MAGT1 300715 Immunodeficiency, X-Linked, With Magnesium Defect, Epstein-Barr Virus Infection, And Neoplasia XLR 2
MAN1B1 604346 MENTAL RETARDATION, AUTOSOMAL RECESSIVE 15 AR 2
MAN2B1 609458 alpha-mannosidosis AR 31
MANBA 609489 Mannosidosis, Beta A, Lysosomal AR 18
MARS2 609728 AR 0
MCCC1 609010 3-Methylcrotonyl-CoA carboxylase 1 deficiency AR 5
MCCC2 609014 3-methylcrotonyl-CoA carboxylase 2 deficiency AR 8
MCEE 608419 Methylmalonyl-coa epimerase deficiency AR 4
MCOLN1 605248 Mucolipidosis type IV AR 9
MFSD8 611124 neuronal ceroid lipofuscinosis type 7; macular dystrophy with central cone involvement AR 14
MGAT2 602616 Congenital disorder of glycosylation, type IIa AR 4
MGME1 615076 mitochondrial DNA depletion syndrome 11 AR 1
MLC1 605908 megalencephalic leukoencephalopathy with subcortical cysts type 1 AR 39
MLPH 606526 Griscelli syndrome, type 3 AR 2
MLYCD 606761 Malonyl-CoA decarboxylase deficiency AR 6
MMAA 607481 methylmalonic aciduria (MMA) of the cblA complementation type AR 7
MMAB 607568 methylmalonic aciduria (MMA) of the cblB complementation type AR 7
MMACHC 609831 Methylmalonic aciduria and homocystinuria, cblC type, digenic type included AR 12
MMADHC 611935 methylmalonic aciduria (MMA) of the cblD complementation type AR 5
MMUT 609058 complete deficiency of methylmalonyl-CoA mutase AR 30
MOCS1 603707 molybdenum cofactor deficiency of complementation group A AR 1
MOCS2 603708 molybdenum cofactor deficiency of complementation group B AR 6
MOGS 601336 congenital disorder of glycosylation type 2b AR 5
MPDU1 604041 congenital disorder of glycosylation type 1f AR 1
MPI 154550 congenital disorder of glycosylation type 1b AR 1
MPV17 137960 mitochondrial DNA depletion syndrome type 6 AR 7
MRPL44 611849 combined oxidative phosphorylation deficiency type 16 AR 0
MRPS22 605810 Combined oxidative phosphorylation deficiency 5 AR 2
MTFMT 611766 Combined oxidative phosphorylation deficiency 15 AR 0
MTHFR 607093 schizophrenia; thrombophilia due to thrombin defect; homocystinuria due to MTHFR deficiency; folate-sensitive neural tube defects AD, AR 35
MTR 156570 homocystinuria-megaloblastic anemia, cblG complementation type; folate-sensitive neural tube defects AR 29
MTRR 602568 Homocystinuria-Megaloblastic Anemia, Cble Complementation Type; folate-sensitive neural tube defects AR 16
MYO5A 160777 Griscelli syndrome, type 1 AR 31
MYOT 604103 Myopathy, spheroid body; Myopathy, myofibrillar, 3; limb-girdle muscular dystrophy type 1A AD 3
NAGA 104170 Schindler disease, type I, III AR 5
NAGLU 609701 mucopolysaccharidosis type IIIB; ? axonal Charcot-Marie-Tooth disease type 2V AD, AR 56
NAGS 608300 N-acetylglutamate synthase deficiency AR 6
NARS2 612803 Combined oxidative phosphorylation deficiency 24 AR 4
NBAS 608025 Short stature, optic nerve atrophy, and Pelger-Huet anomaly; Infantile liver failure syndrome type 2 AR 9
NDUFA1 300078 XLR 10
NDUFA10 603835 AR 3
NDUFA11 612638 AR 5
NDUFA12 614530 Mitochondrial complex I deficiency nuclear type 23 AR 7
NDUFA2 602137 AR 2
NDUFA9 603834 AR 11
NDUFAF1 606934 AR 2
NDUFAF2 609653 Mitochondrial complex I deficiency nuclear type 10 AR 8
NDUFAF4 611776 AR 1
NDUFAF5 612360 AR 9
NDUFAF6 612392 AR 12
NDUFS1 157655 AR 21
NDUFS2 602985 AR 2
NDUFS3 603846 AR 9
NDUFS4 602694 mitochondrial complex I deficiency AR 4
NDUFS6 603848 AR 9
NDUFS7 601825 Mitochondrial complex I deficiency, nuclear type 3 AR 10
NDUFS8 602141 AR 9
NDUFV1 161015 AR 11
NDUFV2 600532 AR 3
NEU1 608272 neuraminidase deficiency AR 7
NEUROD1 601724 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 6 AD 3
NEUROG3 604882 Diarrhea 4, malabsorptive, congenital AR 2
NFU1 608100 Multiple mitochondrial dysfunctions syndrome 1 AR 0
NGLY1 610661 Congenital disorder of deglycosylation AR 11
NHLRC1 608072 Epilepsy, progressive myoclonic 2A (Lafora); Epilepsy, progressive myoclonic 2B (Lafora) AR 3
NOTCH3 600276 CADASIL; Lateral meningocele syndrome AD 55
NPC1 607623 Niemann-Pick disease type C/D AR 249
NPC2 601015 Niemann-Pick disease type C2 AR 17
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 5
NUBPL 613621 AR 9
OAT 613349 Gyrate atrophy of choroid and retina with or without ornithinemia AR 5
OCLN 602876 Band-like calcification with simplified gyration and polymicrogyria AR 2
OCRL 300535 Dent disease type 2; Lowe oculocerebrorenal syndrome XLR 13
OTC 300461 ornithine transcarbamylase deficiency XLR 19
OXCT1 601424 Succinyl CoA:3-oxoacid CoA transferase deficiency AR 5
PAH 612349 phenylketonuria AR 6
PANK2 606157 neurodegeneration with brain iron accumulation type 1; HARP syndrome AR 26
PAX4 167413 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Maturity-onset diabetes of the young, type IX AD, AR 11
PC 608786 pyruvate carboxylase deficiency AR 13
PCCA 232000 propionic acidemia AR 17
PCCB 232050 propionic acidemia AR 14
PCK1 614168 Phosphoenolpyruvate carboxykinase-1, cytosolic, deficiency AR 3
PCSK9 607786 hypercholesterolemia-3 AD 4
PDHA1 300502 Pyruvate dehydrogenase E1-alpha deficiency XLD 14
PDHB 179060 Pyruvate dehydrogenase E1-beta deficiency 9
PDHX 608769 Lacticacidemia due to PDX1 deficiency AR 12
PDP1 605993 Pyruvate dehydrogenase phosphatase deficiency AR 2
PDSS1 607429 Coenzyme Q10 deficiency, primary, 2 AR 26
PDSS2 610564 Coenzyme Q10 deficiency, primary, 3 AR 10
PDX1 600733 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Pancreatic Agenesis, Congenital; MODY type 4 AD, AR 10
PEPD 613230 Prolidase deficiency AR 5
PET100 614770 Mitochondrial complex IV deficiency AR, M 1
PEX1 602136 Peroxisome biogenesis disorder type 1A (Zellweger); Heimler syndrome type 1; peroxisome biogenesis disorder type 1B AR 42
PEX10 602859 peroxisome biogenesis disorder 6A (Zellweger); peroxisome biogenesis disorder 6B AR 8
PEX11B 603867 peroxisome biogenesis disorder 14B (Zellweger) AR 2
PEX12 601758 peroxisome biogenesis disorder type 3B; peroxisome biogenesis disorder type 3A (Zellweger) AR 10
PEX13 601789 peroxisome biogenesis disorder 11A (Zellweger); peroxisome biogenesis disorder 11B AR 12
PEX14 601791 peroxisome biogenesis disorder 13A (Zellweger) AR 19
PEX16 603360 peroxisome biogenesis disorder 8A (Zellweger); Peroxisome biogenesis disorder 8B AR 14
PEX19 600279 peroxisome biogenesis disorder 12A (Zellweger) AR 4
PEX2 170993 peroxisome biogenesis disorder type 5A (Zellweger); peroxisome biogenesis disorder type 5B AR 4
PEX26 608666 peroxisome biogenesis disorder type 7A (Zellweger); peroxisome biogenesis disorder 7B AR 5
PEX3 603164 peroxisome biogenesis disorder 10A (Zellweger) AR 10
PEX5 600414 peroxisome biogenesis disorder 2B (Zellweger); peroxisome biogenesis disorder 2A (Zellweger); Rhizomelic chondrodysplasia punctata, type 5 AR 15
PEX6 601498 peroxisome biogenesis disorder type 4A (Zellweger); peroxisome biogenesis disorder type 4B; Heimler syndrome type 2 AD, AR 35
PEX7 601757 Rhizomelic chondrodysplasia punctata type 1; peroxisome biogenesis disorder type 9B (Zellweger) AR 15
PFKM 610681 Glycogen storage disease type VII AR 17
PGAM2 612931 Glycogen storage disease X AR 6
PGK1 311800 Phosphoglycerate kinase 1 deficiency XLR 6
PGM1 171900 congenital disorder of glycosylation type 1t AR 23
PHKA1 311870 Muscle glycogenosis XLR 15
PHKA2 300798 glycogen storage disease type IX XLR 40
PHKB 172490 Glycogen storage disease IXb; Phosphorylase kinase deficiency of liver and muscle AR 30
PHKG2 172471 Glycogen storage disease IXc AR 14
PHYH 602026 Refsum disease AR 15
PIK3R1 171833 SHORT syndrome; Immunodeficiency 36 AD, AR 3
PKLR 609712 pyruvate kinase deficiency AD, AR 35
PLA2G6 603604 infantile neuroaxonal dystrophy; neurodegeneration with brain iron accumulation 2B; Parkinson disease 14 AR 68
PLCG2 600220 Familial cold autoinflammatory syndrome 3 AD 4
PLIN1 170290 Lipodystrophy, familial partial, type 4 AD 1
PLP1 300401 Pelizaeus-Merzbacher disease; spastic paraplegia 2 XLR 24
PMM2 601785 congenital disorder of glycosylation type 1a AR 3
PNPO 603287 Pyridoxamine 5'-phosphate oxidase deficiency AR 6
PNPT1 610316 Combined oxidative phosphorylation deficiency 13; Deafness, autosomal recessive 70 AR 5
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 50
POLR3A 614258 hypomyelinating leukodystrophy-7 AR 34
POLR3B 614366 hypomyelinating leukodystrophy-8 AR 24
POR 124015 Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis; Disordered Steroidogenesis Due To Cytochrome P450 Oxidoreductase Deficiency AR 11
PPARG 601487 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; OBESITY; Lipodystrophy, familial partial, type 3 AD, AR 2
PPOX 600923 variegate porphyria AD 6
PPT1 600722 neuronal ceroid lipofuscinosis type 1 AR 16
PRF1 170280 familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin; Aplastic Anemia AR 17
PRICKLE1 608500 Epilepsy, progressive myoclonic 1B AR 3
PRKAG2 602743 Wolff-Parkinson-White syndrome; fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease; familial hypertrophic cardiomyopathy 6 AD 19
PRKCD 176977 Autoimmune lymphoproliferative syndrome, type III AR 2
PRODH 606810 Hyperprolinemia, type I; susceptibility to Schizophrenia, 4 AD, AR 6
PSAP 176801 metachromatic leukodystrophy due to SAP-b deficiency; atypical Gaucher disease; Combined SAP deficiency; atypical Krabbe disease AR 24
PSEN1 104311 Pick disease; Dementia, frontotemporal; early-onset familial Alzheimer disease-3; dilated cardiomyopathy-1U; Acne inversa, familial, 3 AD 14
PTF1A 607194 Pancreatic Agenesis 2 AR 3
PTS 612719 Hyperphenylalaninemia, BH4-deficient, A AR 3
PYCR2 616406 hypomyelinating leukodystrophy-10 AR 3
PYGL 613741 glycogen storage disease type 6 AR 36
PYGM 608455 glycogen storage disease type 5 AR 37
QDPR 612676 Hyperphenylalaninemia, BH4-deficient, C AR 13
RAB27A 603868 Griscelli syndrome, type 2 AR 6
RAI1 607642 Smith-Magenis syndrome AD 12
RARS1 107820 hypomyelinating leukodystrophy-9 AR 5
RARS2 611524 pontocerebellar hypoplasia type 6 AR 15
RBCK1 610924 Polyglucosan body myopathy 1 with or without immunodeficiency AR 7
RFT1 611908 congenital disorder of glycosylation type 1n AR 3
RFX6 612659 Mitchell-Riley syndrome AR 30
RNASEH2A 606034 Aicardi-Goutieres syndrome type 4 AR 14
RNASEH2B 610326 Aicardi-Goutieres syndrome type 2 AR 23
RNASEH2C 610330 Aicardi-Goutieres syndrome 3 AR 6
RNASET2 612944 Leukoencephalopathy, cystic, without megalencephaly AR 9
RPIA 180430 AR 0
RRM2B 604712 mitochondrial DNA depletion syndrome 8A; progressive external ophthalmoplegia with mitochondrial DNA deletions 5 AD, AR 21
SAMHD1 606754 Aicardi-Goutieres syndrome type 5; Chilblain lupus type 2 AD, AR 26
SCARB2 602257 Epilepsy, progressive myoclonic 4, with or without renal failure AR 2
SCO1 603644 Mitochondrial complex IV deficiency AR, M 4
SCO2 604272 Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1; Myopia 6 AD, AR 1
SDHA 600857 mitochondrial complex II deficiency; Leigh syndrome; dilated cardiomyopathy-1GG; paragangliomas type 5 AD, AR, M 33
SDHAF1 612848 mitochondrial complex II deficiency AR 5
SDHB 185470 paragangliomas type 4; pheochromocytoma; gastrointestinal stromal tumor; paraganglioma and gastric stromal sarcoma AD 7
SDHD 602690 paragangliomas 1; pheochromocytoma; mitochondrial complex II deficiency; paraganglioma and gastric stromal sarcoma AD, AR 8
SERAC1 614725 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL syndrome). AR 8
SERPINI1 602445 Encephalopathy, familial, with neuroserpin inclusion bodies AD 0
SGSH 605270 mucopolysaccharidosis type IIIA AR 64
SLC16A1 600682 Monocarboxylate transporter 1 deficiency AD, AR 4
SLC16A2 300095 Allan-Herndon-Dudley syndrome XL 11
SLC17A5 604322 infantile sialic acid storage disorder; Salla disease AR 11
SLC19A3 606152 biotin-thiamine-responsive basal ganglia disease AR 13
SLC22A5 603377 systemic primary carnitine deficiency AR 8
SLC25A1 190315 Combined D-2- and L-2-hydroxyglutaric aciduria AR 6
SLC25A12 603667 Epileptic encephalopathy, early infantile, 39 AR 3
SLC25A13 603859 Citrullinemia, Type Ii, Adult-Onset; Citrullinemia, type II, neonatal-onset AR 7
SLC25A15 603861 Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome AR 5
SLC25A20 613698 Carnitine-acylcarnitine translocase deficiency AR 3
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 11
SLC2A1 138140 Dystonia-9; GLUT1 deficiency syndrome; dystonia 18; Epilepsy, idiopathic generalized, suscpetibility to, 12 AD, AR 44
SLC2A2 138160 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Fanconi-Bickel syndrome AD, AR 31
SLC35A1 605634 Congenital disorder of glycosylation, type IIf AR 0
SLC35A2 314375 congenital disorder of glycosylation type 2m XLD 3
SLC35C1 605881 Congenital disorder of glycosylation, type IIc AR 1
SLC3A1 104614 cystinuria AD, AR 15
SLC40A1 604653 Hemochromatosis, type 4 AD 10
SLC4A1 109270 Autosomal dominant distal renal tubular acidosis; resistance to malaria; Renal tubular acidosis, distal, with hemolytic anemia; Spherocytosis, type 4 AD, AR 9
SLC6A8 300036 Cerebral creatine deficiency syndrome type 1 XLR 20
SLC6A9 601019 Glycine encephalopathy with normal serum glycine AR 3
SLC7A7 603593 Lysinuric protein intolerance AR 11
SLC7A9 604144 cystinuria AD, AR 13
SLCO1B1 604843 Hyperbilirubinemia, Rotor type, digenic DiR 5
SLCO1B3 605495 Hyperbilirubinemia, Rotor type, digenic DiR 13
SMPD1 607608 Niemann-Pick disease type A; Niemann-Pick disease type A/B AR 87
SNTA1 601017 long QT syndrome 12 AD 0
SOX10 602229 PCWH syndrome; Waardenburg syndrome type 2E; Waardenburg syndrome, type 4C AD 20
SPART 607111 spastic paraplegia 20 AR 14
SPG11 610844 Amyotrophic lateral sclerosis 5, juvenile; spastic paraplegia type 11; Charcot-Marie-Tooth disease, axonal, type 2X AR 72
SPG7 602783 spastic paraplegia 7 AD, AR 47
SPTA1 182860 Elliptocytosis type 2; Pyropoikilocytosis; Spherocytosis, type 3 AD, AR 4
SPTB 182870 Spherocytosis, type 2; Elliptocytosis 3 AD 9
SRD5A3 611715 congenital disorder of glycosylation type 1q; Kahrizi syndrome AR 1
SSR4 300090 congenital disorder of glycosylation type 1y XLR 1
STAT1 600555 Autosomal recessive Immunodeficiency 31B, mycobacterial and viral infections; Immunodeficiency 31C, autosomal dominant AD, AR 6
STT3A 601134 congenital disorder of glycosylation type 1w AR 2
STT3B 608605 Congenital disorder of glycosylation, type Ix AR 0
STX11 605014 Hemophagocytic lymphohistiocytosis, familial, 4 AR 2
STXBP2 601717 Hemophagocytic lymphohistiocytosis, familial, 5 9
SUCLA2 603921 mitochondrial DNA depletion syndrome 5 AR 15
SUCLG1 611224 mitochondrial DNA depletion syndrome 9 AR 8
SUGCT 609187 AR 1
SUMF1 607939 multiple sulfatase deficiency AR 18
SUOX 606887 Sulfite oxidase deficiency AR 9
SURF1 185620 Leigh syndrome AR, M 15
SYNE1 608441 autosomal recessive spinocerebellar ataxia 8; Emery-Dreifuss muscular dystrophy 4 AD, AR 70
TACO1 612958 Mitochondrial complex IV deficiency AR, M 3
TAT 613018 Tyrosinemia type II AR 5
TAZ 300394 Barth syndrome XLR 6
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 7
TCF4 602272 Pitt-Hopkins syndrome AD 33
TCN2 613441 Transcobalamin II deficiency AR 11
TFR2 604720 hemochromatosis type 3 AR 10
TGFB1 190180 Camurati-Engelmann disease; cystic fibrosis AD, AR 2
TINF2 604319 Revesz syndrome; Dyskeratosis congenita, autosomal dominant 3 AD 2
TK2 188250 mitochondrial DNA depletion syndrome 2 AR 7
TMEM165 614726 Congenital disorder of glycosylation, type IIk AR 0
TMEM70 612418 Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 AR 9
TPK1 606370 Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) AR 5
TPP1 607998 neuronal ceroid lipofuscinosis type 2; autosomal recessive spinocerebellar ataxia type 7 AR 31
TREM2 605086 polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy type 2 AD 1
TREX1 606609 systemic lupus erythematosus; retinal vasculopathy with cerebral leukodystrophy; Aicardi-Goutieres syndrome type 1; chilblain lupus type 1 AD, AR 12
TRPV4 605427 Brachyolmia type 3; Metatropic dysplasia; Spondylometaphyseal dysplasia, Kozlowski type; Hereditary motor and sensory neuropathy, type IIc AD 13
TSFM 604723 Combined oxidative phosphorylation deficiency 3 AR 3
TTC19 613814 nuclear mitochondrial complex III deficiency type 2 AR 13
TUBB4A 602662 dystonia 4; hypomyelinating leukodystrophy-6 AD 8
TUFM 602389 Combined oxidative phosphorylation deficiency 4 AR 4
TUSC3 601385 MENTAL RETARDATION, AUTOSOMAL RECESSIVE 7 AR 1
TWNK 606075 Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Progressive external ophthalmoplegia, autosomal dominant, 3 AD, AR 4
TYMP 131222 mitochondrial DNA depletion syndrome 1 AR 13
TYROBP 604142 polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy type 1 AR 5
UCP2 601693 0
UGT1A1 191740 Gilbert syndrome; Crigler-Najjar syndrome type I; familial transient neonatal hyperbilirubinemia; serum level of Bilirubin, QTL1; Crigler-Najjar syndrome type II AR 24
UMPS 613891 Orotic aciduria AR 6
UNC13D 608897 familial hemophagocytic lymphohistiocytosis 3 AR 16
UQCRQ 612080 Mitochondrial complex III deficiency, nuclear type 4 AR 0
UROD 613521 hepatoerythropoietic porphyria AD, AR 3
UROS 606938 Porphyria, congenital erythropoietic AR 7
WDR45 300526 neurodegeneration with brain iron accumulation 5 XLD 9
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 22
ZFP57 612192 Diabetes mellitus, transient neonatal, 1 AD 7
ZFYVE26 612012 spastic paraplegia type 15 AR 60

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.