DHMN VA
SPINAL MUSCULAR ATROPHY, DISTAL, TYPE V
SPINAL MUSCULAR ATROPHY, DISTAL, WITH UPPER LIMB PREDOMINANCE
NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE V
DSMAVA
HMN VA
DHMN5A
SPINAL MUSCULAR ATROPHY, DISTAL, TYPE VA
NEUROPATHY, DISTAL HEREDITARY MOTOR, TYPE VA
HMN5A
DSMAV
HMN5
Meadows and Marsden (1969) reported 3 sibs with a form of distal muscular atrophy confined largely to the upper extremities. All had weakness of the hands since early childhood, manifest by difficulty writing. The condition worsened significantly much ... Meadows and Marsden (1969) reported 3 sibs with a form of distal muscular atrophy confined largely to the upper extremities. All had weakness of the hands since early childhood, manifest by difficulty writing. The condition worsened significantly much later in life, in the sixth and seventh decades. Hand weakness and atrophy were apparent in all, and 2 sibs had lower limb weakness with hyporeflexia/areflexia; the remaining sib had hyporeflexia/areflexia without lower limb weakness. EMG and muscle biopsy confirmed a neurogenic disorder. The mode of inheritance was unclear. Christodoulou et al. (1995) identified a large 5-generation Bulgarian family from Burgass with an autosomal dominant distal spinal muscular atrophy (dSMA) with upper limb predominance. Afflicted members had weakness and wasting which was more prominent in the upper limbs and more selectively involved the thenar muscles and the first dorsal interossei. They had clinical information on 114 family members, of whom 30 were affected. The disease commenced with hand involvement at a mean age of 17 years (median 16 years). In 40% of patients, symptoms subsequently developed in their feet within about 2 years. In 1 branch of the family, mild pyramidal features and, rarely, up-going plantar responses were observed. There were not sensory symptoms or signs except for slightly reduced vibratory sense in the feet in 10% of the patients. Progression of the disease was very slow, with patients still ambulant at the age of 64. Electrophysiologic investigations showed reduced or, in severely wasted muscles, unobtainable compound motor action potentials. Motor conduction velocities and distal latencies were normal, except in severely wasted muscles, where the former were reduced. Christodoulou et al. (1995) concluded that the family fell into the type V category of distal spinal muscular atrophy according to Harding (1993), who proposed a classification into 7 types of distal SMA according to their clinical and genetic features. The family was similar to the one reported by Lander et al. (1976), but differed in that weakness and wasting were more severe in the thenar muscles and first dorsal interossei. The family was considered to be different from the families with Silver syndrome described by Silver (1966) and by van Gent et al. (1985) in that most of their patients also had brisk reflexes and signs of spasticity in addition to hand weakness. Sambuughin et al. (1998) reported a family in which autosomal dominant CMT2D and distal spinal muscular atrophy type V segregated in the same kindred. All 17 affected members had bilateral weakness and wasting in thenar and first dorsal interossei muscles starting commonly with cold-induced cramps in the hands in their late teens. The mean age at onset was 18 years (range 12 to 36) and progression of illness was very slow. DSMAV was diagnosed in 11 patients based on the presence of hand and peroneal muscle weakness and atrophy without sensory deficits. CMT2D was diagnosed in 6 other patients based on the presence of weakness and atrophy in the same muscle groups, hypoactive knee and ankle reflexes, stocking and glove distribution sensory loss, and reduced sensory nerve action potential amplitudes. Antonellis et al. (2003) reported an Algerian Sephardic Jewish family with autosomal dominant DSMAV. A father and daughter had bilateral hand amyotrophy and weakness, particularly in the thenar and dorsal interosseus muscles. Motor and sensory nerve conduction velocities were normal. Van de Warrenburg et al. (2006) reported 2 unrelated Dutch families with overlapping Silver syndrome and distal motor neuropathy caused by the same BSCL2 mutation (N88S; 606158.0013). The first family contained 5 affected individuals spanning 3 generations. All presented with pes cavus and foot of leg muscle weakness and atrophy between 11 and 26 years of age. There was slow progression, with gradually evolving lower limb hypertonia and hyperreflexia with extensor plantar responses without prominent spasticity. Two patients also developed weakness and atrophy of the first dorsal interosseus and abductor pollicis brevis muscles without involvement of the hypothenar muscles. In the second family, there were multiple affected individuals spanning 3 generations. Age at onset was before age 20 years. About half of the patients presented with foot or leg muscle weakness and atrophy, whereas the other half presented with hand muscle weakness and atrophy. Most developed hyperreflexia with extensor plantar responses; spasticity was observed in older patients. Van de Warrenburg et al. (2006) emphasized the phenotypic variability and incomplete penetrance of some symptoms. Brusse et al. (2009) reported 12 members of a large 3-generation Dutch family with phenotypic overlap between Silver syndrome and distal HMN5 who carried a heterozygous N88S mutation in the BSCL2 gene. The phenotype was variable, and the distribution of muscle weakness and atrophy included predominantly the feet (in 4), the hands (in 1), or both upper and lower extremities (in 4). Three individuals showed evidence of pyramidal features, including spasticity, hyperrflexia, and extensor plantar responses. Severity of the disease ranged from adolescent patients with disabling muscle weakness to an elderly patient with only mild weakness of the ankle dorsiflexors and bilateral pes cavus. Brusse et al. (2009) noted the extreme phenotypic variability associated with the N88S mutation in their family and in those reported by Auer-Grumbach et al. (2005) and van de Warrenburg et al. (2006), who also carried the N88S mutation, and suggested the presence of other genetic or environmental factors. In their family, Brusse et al. (2009) used genomewide linkage analysis to identify a candidate disease modifier on chromosome 16p13.3-p13.12 that was shared by all 12 affected individuals (maximum lod score of 3.28). One family member without the N88S mutation but with the chromosome 16p haplotype showed mild electrophysiologic abnormalities. Brusse et al. (2009) postulated that a locus on chromosome 16p may contain a disease modifier in their family.
Irobi et al. (2004) reviewed the molecular genetics of the distal motor neuropathies.
- Mutations in the GARS Gene
In the families with DSMAV reported by Christodoulou et al. (1995) and Antonellis et al. ... Irobi et al. (2004) reviewed the molecular genetics of the distal motor neuropathies. - Mutations in the GARS Gene In the families with DSMAV reported by Christodoulou et al. (1995) and Antonellis et al. (2003) and the family with both DSMAV and CMT2D reported by Sambuughin et al. (1998), Antonellis et al. (2003) identified mutations in the GARS gene (600287.0002-600287.0004). Dubourg et al. (2006) identified a mutation in the GARS gene (G526R; 600287.0004) in 12 affected members from 3 French families of Sephardic Jewish origin with HMN type V. Four mutation carriers were clinically asymptomatic, suggesting incomplete penetrance. Most presented with distal upper limb involvement between the second and fourth decades; none had sensory involvement. Haplotype analysis suggested a founder effect. - Mutations in the BSCL2 Gene In affected members of 1 Italian, 1 English, and 8 Austrian families with DSMAV, including the one reported by Auer-Grumbach et al. (2000), Windpassinger et al. (2004) identified a heterozygous asn88-to-ser mutation in the BSCL2 gene (N88S; 606158.0013). In the same study, Windpassinger et al. (2004) also identified mutations in the BSCL2 gene in patients with Silver syndrome, indicating that the 2 disorders are extreme phenotypes with the same genetic etiology. The large affected Austrian kindred comprised 4 family branches with Silver syndrome and 8 family branches with DSMAV; all affected Austrian patients had the N88S mutation in the BSCL2 gene. By in vitro functional expression analysis, Ito and Suzuki (2007) demonstrated that the N88S and S90L mutations in the BSCL2 gene disrupt glycosylation of the seipin protein. Overexpressed mutant seipin was highly ubiquitinated and degraded by the proteasome, and improper glycosylation exacerbated endoplasmic reticulum (ER) retention. Mutant proteins activated the unfolded protein response (UPR), resulting in apoptotic cell death through ER stress. Ito and Suzuki (2007) concluded that the N88S and S90L mutations, which result in motor neuron disease, have a gain-of-function effect, resulting in conformational protein changes, activation of the UPR, cell death, and neurodegeneration. Ito and Suzuki (2009) provided a review.
The phenotypic spectrum of BSCL2-related neurologic disorders includes Silver syndrome and variants of Charcot-Marie-Tooth disease type 2, distal hereditary motor neuropathy (dHMN) type V, and spastic paraplegia 17. The common clinical signs and symptoms of these BSCL2-related neurologic disorders include, among others, the following:...
DiagnosisClinical DiagnosisThe phenotypic spectrum of BSCL2-related neurologic disorders includes Silver syndrome and variants of Charcot-Marie-Tooth disease type 2, distal hereditary motor neuropathy (dHMN) type V, and spastic paraplegia 17. The common clinical signs and symptoms of these BSCL2-related neurologic disorders include, among others, the following:Onset of symptoms from the first to the seventh decade (range from age 6 to 66 years; mean age19 years)Slow disease progressionUpper motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responsesLower motor neuron involvement: amyotrophy (wasting) of the peroneal muscles and the small muscles of the hand (particularly the thenar and dorsalis interosseus I muscles) that is frequently unilateralUsually normal sensation except for pallesthesia (i.e., abnormal vibration sense)Pes cavus and other foot deformitiesTestingElectrophysiologic studies are useful in the diagnosis of BSCL2-related neurologic disorders:Reduced compound motor action potentials (CMAP) in the lower limbs indicate primarily axonal nerve damage. Marked chronodispersion of the CMAP is found.Motor nerve conduction velocities (MNCV) are sometimes in the demyelinating range (<37 m/sec) pointing to additional demyelination of the peripheral nerves. Partial conduction blocks may occur. Note: In the upper limbs, changes of the MNCV and CMAP are more frequently seen in the median nerve than in the ulnar nerve.Median and sural sensory nerve conduction velocities (SNCV) do not show significant changes, but reduction of the sensory nerve action potentials (SNAP) in individuals with advanced disease strongly suggests that BSCL2 mutations also lead to axonal damage of the sensory nerves.Electromyography usually reveals chronic neurogenic disturbance with high potential amplitudes [Auer-Grumbach et al 2000].Sural nerve biopsy shows mild loss of myelinated fibers and fiber regeneration [Chen et al 2009, Luigetti et al 2010]. The diameter histogram shows a reduction in small fibers (diameter <10 μm). Molecular Genetic TestingGene. BSCL2 is presently the only gene in which mutations are known to cause BSCL2-related neurologic disorders.Clinical testingSequence analysis and sequence analysis of select exons. See Testing Strategy.Deletion/duplication analysis. Because no deletions or duplications of BSCL2 have been reported to cause BSCL2-related neurologic disorders/seipinopathy, the usefulness of such testing is unknown. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Table 1. Summary of Molecular Genetic Testing Used in BSCL2-Related Neurologic Disorders/SeipinopathyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityBSCL2Sequence analysis of select exonsExon 3 (containing c.263A>G and c.269C>T)100% for mutations in exon 3Clinical Sequence analysis Sequence variants 2100% 3Deletion / duplication analysis 4Exonic or whole-gene deletionsUnknown; none reported1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Because this disorder is defined by the presence of a causative mutation in BSCL2, the mutation detection rate is expected to be 100%; the rate would be less if any deletion/duplication mutations were found to cause the disorder.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband requires identification of a BSCL2 mutation on molecular genetic testing. Typically, sequence analysis of BSCL2 begins with testing exon 3 for p.Asn88Ser and p.Ser90Leu, the only two mutations associated with BSCL2-related neurologic disorders to date. If neither mutation is detected, all coding exons are sequenced.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersIn addition to BSCL2-related neurologic disorders, the other phenotype associated with mutations in BSCL2 is Berardinelli-Seip congenital lipodystrophy type 2. Berardinelli-Seip congenital lipodystrophy (BSCL) type 1 and type 2, which are inherited in an autosomal recessive manner, are characterized by lipoatrophy affecting the trunk, limbs, and face; acromegaloid features; hepatomegaly; elevated serum concentration of triglycerides; and insulin resistance. Hypertrophic cardiomyopathy occurs in 20%-25% of affected individuals and is a significant cause of morbidity and mortality. Notably, abnormality of motor neurons has not been reported in Berardinelli-Seip congenital lipodystrophy type 2.
BSCL2-related neurologic disorders affect both the lower and upper motor neurons. Detailed clinical and electrophysiologic studies in 90 individuals with the p.Asn88Ser mutation showed incomplete penetrance, clinical intrafamilial variability with several phenotypic subtypes being reported (even within the same family), and a broad variation of disease severity, suggesting a subdivision into the following six main phenotypes (subtypes 1-6), all of which can be seen in the same family [Auer-Grumbach et al 2005]:...
Natural HistoryBSCL2-related neurologic disorders affect both the lower and upper motor neurons. Detailed clinical and electrophysiologic studies in 90 individuals with the p.Asn88Ser mutation showed incomplete penetrance, clinical intrafamilial variability with several phenotypic subtypes being reported (even within the same family), and a broad variation of disease severity, suggesting a subdivision into the following six main phenotypes (subtypes 1-6), all of which can be seen in the same family [Auer-Grumbach et al 2005]:Subtype 1. No signs or symptoms. No clinical or electrophysiologic abnormalities are present.Subtype 2. Clinical signs but no symptoms. Suggestive clinical signs include foot deformity, mild asymmetric thenar wasting, brisk lower-limb deep-tendon reflexes (DTRs), and/or electrophysiologic abnormalities.Subtype 3. Distal hereditary motor neuropathy (dHMN) type V phenotype. Symptoms are exclusively or predominantly symmetric or unilateral muscle weakness and wasting in the small muscles of the hand. Gait disturbances may occur later. Muscle tone is normal; tendon reflexes may be preserved or slightly brisk.Subtype 4. Silver syndrome phenotype [Silver 1966]. Findings are mild-to-severe symmetric or unilateral amyotrophy of the small muscles of the hand, variable spasticity of the lower limbs, and other signs of pyramidal tract disturbance (very brisk tendon reflexes and/or extensor plantar responses and/or increased muscle tone).Subtype 5. Charcot Marie Tooth type 2 (spinal CMT) phenotype. Findings are distal muscle weakness and wasting of the lower limbs and, to a lesser degree, of the upper limbs. Muscle tone is normal and tendon reflexes are usually preserved or slightly brisk. Depending on the absence or presence of clinical and electrophysiologic sensory abnormalities, affected individuals may show spinal CMT syndrome or hereditary motor and sensory neuropathy (HMSN) type II.Subtype 6. Hereditary spastic paraplegia (HSP) phenotype. Findings are absence of weakness or wasting of the small hand muscles, but presence of spastic paraparesis in the lower limbs manifest as EITHER:Pure hereditary spastic paraparesis (pHSP) when no additional clinical or electrophysiologic features (except foot deformity) are present; OR Complicated hereditary spastic paraparesis (cHSP) when spasticity is accompanied by amyotrophy of the distal muscles of the legs and/or pathologic nerve conduction velocities. This latter group may also be diagnosed as hereditary motor and sensory neuropathy (HMSN) type V. Most affected individuals develop symptoms in the second decade of life, but some first notice symptoms as late as the seventh decade. Only a few persons have signs before age ten years. In some individuals with mild disease, the age at onset cannot be determined as they are not aware of being affected. Disease progression is slow.Tendon reflexes are normal in the upper extremities. Patellar and Achilles tendon reflexes are rarely absent or diminished. Most individuals have preserved or even brisk reflexes, which correspond to increased muscle tone. Affected individuals often present with other signs of pyramidal tract involvement such as extensor plantar responses. Individuals with spasticity in the lower limbs often complain of leg stiffness and muscle cramps.Hand muscle involvement is a major feature. Weakness that is often more evident in one hand than the other and wasting of the thenar and dorsalis interosseus I muscles often result in a characteristic adduction position of the thumb and difficulty with handwriting. In advanced stages of the disease, camptodactyly (fixed flexion deformity of the fingers) can be a significant finding in some, but not all, affected individuals. The predilection for these two muscle groups and the left-right asymmetry (which does not correlate with handedness in the affected individual) remain unexplained. Mild-to-severe gait abnormalities are often observed and result from: (1) wasting and weakness of the distal muscles of the lower limbs leading to a steppage gait, (2) stiffness and spasticity, or (3) both.Foot deformity is present in the majority of individuals and may vary from mild to severe pes cavus, congenital pes planus, hammertoes, or clubfeet.People with this disorder have a generally normal life expectancy.
Individuals with the missense p.Asn88Ser BSCL2 mutation (in which the amino acid asparagine required for N-glycosylation is exchanged) usually remain ambulatory and active up to old age. In many individuals, the phenotype is dominated by subtypes 2, 3, or 5 [Auer-Grumbach et al 2000]....
Genotype-Phenotype CorrelationsIndividuals with the missense p.Asn88Ser BSCL2 mutation (in which the amino acid asparagine required for N-glycosylation is exchanged) usually remain ambulatory and active up to old age. In many individuals, the phenotype is dominated by subtypes 2, 3, or 5 [Auer-Grumbach et al 2000].Individuals with the p.Ser90Leu BSCL2 mutation exhibit more severe phenotypes (subtypes 4 and 6). Some of these individuals may become wheelchair bound during the second decade [Irobi et al 2004a].Null mutations in BSCL2 are associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy.
Other types of axonal neuropathies (CMT2), variants of amyotrophic lateral sclerosis (ALS), or spastic paraplegia (Strumpell-Lorrain disease) may mimic BSCL2-related neurologic disorders. (See Charcot-Marie-Tooth Hereditary Neuropathy Overview, Hereditary Spastic Paraplegia Overview.) ...
Differential DiagnosisOther types of axonal neuropathies (CMT2), variants of amyotrophic lateral sclerosis (ALS), or spastic paraplegia (Strumpell-Lorrain disease) may mimic BSCL2-related neurologic disorders. (See Charcot-Marie-Tooth Hereditary Neuropathy Overview, Hereditary Spastic Paraplegia Overview.) The differential diagnosis for subtypes of BSCL2-related neurologic disorders includes the following:Subtype 3. Charcot-Marie-Tooth neuropathy type 2D/distal spinal muscular atrophy type V (dSMA V), caused by mutations in GARS, the gene encoding glycyl-tRNA synthetase [Antonellis et al 2003]Subtype 4 Juvenile ALS type 4, caused by mutations in SETX, the gene encoding senataxin [Chen et al 2004] (see ALS Overview, ALS4)SPG3a, caused by mutations in SPG3, encoding atlastin [Scarano et al 2005]. See also ALS Overview.Subtype 5 Charcot-Marie-Tooth Neuropathy Type 2 Spinal CMT (dHMN II) caused by mutations in HSP22, the gene encoding the small heat-shock protein 22 [Irobi et al 2004b] Juvenile ALS type 4 caused by mutations in SETX [Chen et al 2004] (see ALS Overview, SETX-Related ALS)Subtype 6. Genes responsible for pure and complicated autosomal dominant hereditary spastic paraplegia (see Hereditary Spastic Paraplegia Overview) and hereditary motor and sensory neuropathy type V (HMSN V) (gene unknown).Other conditions to be considered include acquired motor neuron disorders such as multifocal motor neuropathy and amyotrophic lateral sclerosis and entrapment syndromes of the upper extremities such as carpal tunnel syndrome and compression of ulnar nerve.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with BSCL2-related neurologic disorders, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with BSCL2-related neurologic disorders, the following evaluations are recommended:Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and deep tendon reflex EMG with NCV Complete family history Molecular genetic testingGenetics consultationTreatment of ManifestationsTreatment remains symptomatic and affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, medical geneticists, and physical and occupational therapists.Physiotherapy is appropriate.Orthopedic treatment includes orthopedic shoes and calipers (polypropylene devices that fit between the thighs and hold the legs and hips in a balanced position for standing, used in conjunction with crutches or a walker) to stabilize gait. Foot deformities are corrected by surgical treatment.Prevention of Primary ManifestationsCurrently, no treatment for BSCL2-related neurologic disorders that reverses or slows the natural disease process exists.Prevention of Secondary ComplicationsEarly regular physiotherapy can prevent contractures to a certain extent.SurveillanceAnnual neurologic evaluation of gait, strength, muscular atrophy, and deep tendon reflexes by a neurologist is appropriate.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. BSCL2-Related Neurologic Disorders/Seipinopathy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDBSCL211q12.3SeipinIPN Mutations, BSCL2 HSP mutation database BSCL2 homepage - Leiden Muscular Dystrophy pages BSCL2 homepage - Mendelian genesBSCL2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for BSCL2-Related Neurologic Disorders/Seipinopathy (View All in OMIM) View in own window 270685SPASTIC PARAPLEGIA 17, AUTOSOMAL DOMINANT; SPG17 600794NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE VA; HMN5A 606158BSCL2 GENE; BSCL2Normal allelic variants. BSCL2 has 11 exons spanning approximately 17 kb of genomic DNA.Pathologic allelic variants. Two missense mutations have been detected in individuals with BSCL2-related neurologic disorders (see Table 2). No other mutations leading to BSCL2-related neurologic disorders have been detected; other reported mutations lead to Berardinelli-Seip congenital lipodystrophy .Table 2. Selected BSCL2 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences c.263A>Gp.Asn88SerNM_032667.6 NP_116056.3c.269C>Tp.Ser90LeuSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal gene product. The function of seipin, a 398-amino acid residue integral membrane protein of the endoplasmic reticulum (ER), is unknown.Abnormal gene product. The p.Asn88Ser and p.Ser90Leu mutations disrupt the N-glycosylation motif and appear to result in proteins that are improperly folded. Furthermore, mutant proteins abnormally accumulate in the ER and eventual lead to cell death [Ito & Suzuki 2007]. The Asn88Ser seipin transgenic mice develop a progressive spastic motor deficit and neurogenic muscular atrophy, recapitulating the phenotype of patients with seipinopathy [Yagi et al 2011].