Publications about genetic testing for neurological disorders
  1. SMN-negative spinal muscular atrophy panel

SMN-negative spinal muscular atrophy panel

August 03, 2018

Disease summary:

Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy. The onset of muscle weakness ranges from the prenatal period to adolescence or young adulthood, with infantile-onset SMA being the most common genetic cause of infant mortality3.

Although the majority of SMA cases (>95%) are caused by homozygous deletions of exon 7 and/or exon 8 in the SMN1 gene1, 2, other genes have also been associated with SMA. These diseases must be considered in the differential diagnosis when SMN1 testing is negative. Other genes to be tested include ATP7A, BICD2, BSCL2, CHCHD10, DCTN1, DNAJB2, DYNC1H1, EXOSC3, EXOSC8, FBXO38, GARS, HSPB1, HSPB3, HSPB8, IGHMBP2, TRPV4, UBA1 and VAPB  1, 4, 5 (Table 1). 

Autosomal recessive, autosomal dominant, X-linked inheritance

4-10/1,000,000 (incidence of SMN-negative SMA)1, 6, 7, 8

Major clinical symptoms of SMA 1, 2, 3:

  • Progressive muscle weakness and atrophy
  • The onset ranges from before birth to adolescence/young adulthood
  • Poor weight gain, growth failure

Other clinical findings1, 2, 3:

  • Severe neonatal or later-onset hypotonia
  • Respiratory failure, abdominal breathing
  • Joint contractures, scoliosis
  • Facial weakness, tongue fasciculations

Specific clinical symptoms of the various differential diagnoses  are listed in Table 1.

  • Presence of the specific clinical features
  • Identification of pathogenic variant(s) in one of the associated genes (ATP7A, BICD2, BSCL2, CHCHD10, DCTN1, DNAJB2, DYNC1H1, EXOSC3, EXOSC8, FBXO38, GARS, HSPB1, HSPB3, HSPB8, IGHMBP2, TRPV4, UBA1, VAPB)

There is no cure for SMN-negative spinal muscular atrophy to date, but symptomatic treatments can relieve symptoms 1, 2, 3:

  • Nutritional support (gastronomy tube)
  • Respiratory support
  • Surgical repair for scoliosis and joint problems
  • Prader-Willi syndrome
  • Congenital myotonic dystrophies
  • Myotonic dystrophy type 1
  • Congenital myasthenic syndromes
  • Duchenne/Becker muscular dystrophy
  • Amyotrophic lateral sclerosis
  • Spinal and bulbar muscular atrophy

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • SMN-negative spinal muscular atrophy NGS Panel Plus which includes sequencing of the genes ATP7A, BICD2, BSCL2, CHCHD10, DCTN1, DNAJB2, DYNC1H1, EXOSC3, EXOSC8, FBXO38, GARS, HSPB1, HSPB3, HSPB8, IGHMBP2, TRPV4, UBA1, VAPB
  • SMN-negative spinal muscular atrophy NGS Panel Plus + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data
  • Individuals with a positive family history of SMN-negative spinal muscular atrophy
  • Individuals with symptoms suggestive of SMA with previously negative SMN1 and SMN2 testing (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of SMN-negative spinal muscular atrophy can allow for genetic counseling and may direct medical management.

Table 1. Overview of the genes in CENTOGENE´s SMN negative spinal muscular atrophy panel:

Gene (OMIM)Associated disease (OMIM) Inheritance Clinical features
ATP7A (300011) Spinal muscular atrophy, distal, X-linked 3 (300489); Occipital horn syndrome (304150); Menkes disease (309400);  XLR Early onset growth retardation, distal lower limb weakness, gait abnormalities, foot deformity, muscular atrophy, hypotonia, seizures, failure to thrive, “occipital horns”
BICD2 (609797) Spinal muscular atrophy, lower extremity-predominant, 2, (615290) AD Early-childhood onset, muscle weakness and atrophy of lower extremity, delayed walking, waddling gait, loss of distal reflexes, foot deformities, spasticity
BSCL2 (606158) Neuropathy, distal hereditary motor, type VA (600794); Silver spastic paraplegia syndrome (270685); Encephalopathy, progressive, with or without lipodystrophy (615924); Lipodystrophy, congenital generalized, type 2 (269700) AD, AR Early onset, slow progression of muscle weakness and wasting, gait disturbance, mild to severe spasticity, hyperreflexia, amyotrophy, pes cavus and other foot deformities
CHCHD10 (615903) Spinal muscular atrophy, Jokela type (615048); Myopathy, isolated mitochondrial (616209); Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (615911)  AD Adult onset slowly progressive weakness, amyotrophy, exercise intolerance, behavioral changes, language disturbances, cognitive decline, gait ataxia, dysarthria/dysphagia, nystagmus
DCTN1 (601143) Neuropathy, distal hereditary motor, type VIIB (607641); Perry syndrome (168605); Amyotrophic lateral sclerosis, susceptibility to (105400) AD, AR Adult onset, parkinsonian symptoms, hypoventilation, depression, weight loss, autonomic abnormalities
DNAJB2 (604139) Spinal muscular atrophy, distal, autosomal recessive, 5 (614881)  AR Young adult onset of slowly progressive distal muscle weakness and atrophy, difficulties walking, gait impairment, loss of reflexes 
DYNC1H1 (600112) Spinal muscular atrophy, lower extremity-predominant 1 (158600); Charcot-Marie-Tooth disease, axonal, type 20 (614228); Mental retardation, autosomal dominant (614563)  AD Childhood onset, spinal muscular atrophy, muscle weakness, gait abnormalities, peripheral neuropathy
EXOSC3 (606489) Pontocerebellar hypoplasia, type 1B (614678) AR Neonatal onset, progressive muscle weakness, microcephaly, global developmental delay, severe hypotonia, respiratory insufficiency, cerebellar atrophy, joint contractures
EXOSC8 (606019) Pontocerebellar hypoplasia, type 1C (616081) AR Neonatal/infantile onset, severe muscle weakness, failure to thrive, delayed psychomotor development, visual and hearing impairment, respiratory failure, cerebellar hypoplasia
FBXO38 (608533) Neuronopathy, distal hereditary motor, type IID (615575) AD Juvenile onset of slowly progressive distal lower limb weakness, muscle atrophy, difficulty walking, loss of ankle reflexes
GARS (600287) Charcot-Marie-Tooth disease, type 2D (601472); Neuropathy, distal hereditary motor, type VA  (600794) AD Early onset, distal muscular atrophy in upper extremities, hand muscle weakness, difficulty writing, hyporeflexia/areflexia
HSPB1 (602195) Charcot-Marie-Tooth disease, axonal, type 2F (606595); Neuropathy, distal hereditary motor, type IIB (608634) AD Adult onset, slowly progressive muscle weakness and atrophy in distal lower limb muscles, walking difficulties, depressed tendon reflexes
HSPB3 (604624) Neuronopathy, distal hereditary motor, type IIC (613376) AD Adult onset distal motor neuropathy, slowly progressive muscle weakness, frequent falls, instability, hand weakness
HSPB8 (608014) Charcot-Marie-Tooth disease, axonal, type 2L (608673); Neuropathy, distal hereditary motor, type IIA (158590) AD Adult onset, distal muscular weakness and atrophy, hyporeflexia, sensory loss, slow progression
IGHMBP2 (600502) Charcot-Marie-Tooth disease, axonal, type 2S (616155); Neuropathy, distal hereditary motor, type VI (604320) AR Early onset, progressive distal motor weakness and atrophy, severe respiratory distress, diaphragmatic paralysis, peripheral neuropathy
TRPV4 (605427) Spinal muscular atrophy, distal, congenital nonprogressive (600175); Hereditary motor and sensory neuropathy, type IIc (606071); Scapuloperoneal spinal muscular atrophy (181405); Brachyolmia type 3 (113500); Digital arthropathy-brachydactyly, familial (606835); Metatropic dysplasia (156530); SED, Maroteaux type (184095); Spondylometaphyseal dysplasia, Kozlowski type (184252)  AD Early onset, progressive peripheral neuropathy, progressive muscle weakness and atrophy, laryngeal dysfunction, respiratory dysfunction, joint contractures, skeletal anomalies
UBA1 (314370) Spinal muscular atrophy, X-linked 2, infantile (301830) XLR Neonatal onset of severe hypotonia, areflexia, multiple congenital contractures (arthrogryposis), scoliosis, chest deformities, hypotonia, micrognatia, ptosis, infantile death
VAPB (605704) Spinal muscular atrophy, late-onset, Finkel type (182980); Amyotrophic lateral sclerosis 8 (608627)  AD Adult onset, proximal muscular atrophy, absent tendon reflexes, generalized fasciculations