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BSCL2-Related Neurologic Disorders/Seipinopathy

Includes: Distal Hereditary Motor Neuropathy Type V, Spastic Paraplegia 17, Silver Syndrome, Variants of Charcot-Marie-Tooth Disease Type 2
, MD, PhD
Department of Neurology, School of Medicine
Keio University
Tokyo, Japan

Initial Posting: ; Last Revision: June 7, 2012.

Summary

Disease characteristics. The 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. Features of these disorders include onset of symptoms ranging from the first to the seventh decade, slow disease progression, upper motor neuron involvement (gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses), lower motor neuron involvement (amyotrophy of the peroneal muscles and small muscles of the hand), abnormal vibration sense, and pes cavus and other foot deformities. Disease severity is variable among and within families.

Diagnosis/testing. The BSCL2-related neurologic disorders are diagnosed by clinical findings, electrophysiologic studies, and molecular genetic testing. Molecular genetic testing of BSCL2 detects 100% of mutations in individuals with these disorders.

Management. Treatment of manifestations: Symptomatic treatment includes physiotherapy, orthopedic shoes, and calipers to stabilize gait. Foot deformities may be corrected with surgery.

Surveillance: Annual neurologic evaluation of gait, strength, and muscular atrophy by a neurologist.

Genetic counseling. BSCL2-related neurologic disorders are inherited in an autosomal dominant manner. Each child of an individual with a BSCL2-related neurologic disorder has a 50% chance of inheriting the mutation. Penetrance is incomplete, with more than 20% of individuals with the mutation showing no clinical abnormalities or only minor clinical signs. Prenatal testing for pregnancies at increased risk is possible in families in which the disease-causing mutation is known; however, requests for prenatal testing for adult-onset disorders are not common.

Diagnosis

Clinical Diagnosis

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:

  • Onset of symptoms from the first to the seventh decade (range from age 6 to 66 years; mean age19 years)
  • Slow disease progression
  • Upper motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses
  • Lower 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 unilateral
  • Usually normal sensation except for pallesthesia (i.e., abnormal vibration sense)
  • Pes cavus and other foot deformities

Testing

Electrophysiologic 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 Testing

Gene. BSCL2 is presently the only gene in which mutations are known to cause BSCL2-related neurologic disorders.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in BSCL2-Related Neurologic Disorders/Seipinopathy

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
BSCL2Sequence analysis of select exonsExon 3 (containing c.263A>G and c.269C>T)100% for mutations in exon 3
Sequence analysis Sequence variants 2100% 3
Deletion / duplication analysis 4Exonic or whole-gene deletionsUnknown; none reported

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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 Strategy

To 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.

Clinical Description

Natural History

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]:

  • 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.

Genotype-Phenotype Correlations

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].

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.

Penetrance

Reduced penetrance for BSCL2-related neurologic disorders has been shown by Patel et al [2001] and Windpassinger et al [2003]. A detailed genotype-phenotype correlation study in 90 individuals with the p.Asn88Ser mutation demonstrated that 24.4% of individuals with the mutation remained asymptomatic (subtype 1) or were only subclinically affected (subtype 2) [Auer-Grumbach et al 2005].

Anticipation

Anticipation has not been observed.

Nomenclature

Silver syndrome was first described in 1966 in two British families [Silver 1966].

Prevalence

The prevalence of BSCL2-related neurologic disorders/seipinopathy is unknown. The result of screening of BSCL2 for exon 3 mutations indicates that the p.Asn88Ser and p.Ser90Leu mutations are not a common cause of sporadic adult-onset upper motor neuron syndrome [Brugman et al 2009]. To date, approximately 30 families worldwide with BSCL2 mutations p.Asn88Ser and p.Ser90Leu have been identified and described [Ito & Suzuki 2009]. Dierick et al [2008] carried out genetic analyses in a cohort of 112 individuals with a clinical diagnosis of dHMN and found that mutation in BSCL2 is one of the most common causes of dHMN (7%) (see Differential Diagnosis).

Differential Diagnosis

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.)

The differential diagnosis for subtypes of BSCL2-related neurologic disorders includes the following:

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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 testing
  • Genetics consultation

Treatment of Manifestations

Treatment 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 Manifestations

Currently, no treatment for BSCL2-related neurologic disorders that reverses or slows the natural disease process exists.

Prevention of Secondary Complications

Early regular physiotherapy can prevent contractures to a certain extent.

Surveillance

Annual neurologic evaluation of gait, strength, muscular atrophy, and deep tendon reflexes by a neurologist is appropriate.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

BSCL2-related neurologic disorders/seipinopathy are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with a BSCL2-related neurologic disorder have an affected parent.
  • A proband with a BSCL2-related neurologic disorder may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include detailed clinical and electrophysiologic studies and molecular genetic testing to exclude reduced penetrance or variable expressivity.

Note: (1) Although most individuals diagnosed with a BSCL2-related neurologic disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, sibs have a 50% chance of inheriting the mutation. However, penetrance is incomplete and 24.4% of individuals with mutations are asymptomatic.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband. Each child of an individual with a BSCL2-related neurologic disorder has a 50% chance of inheriting the mutation. However, penetrance is incomplete and 24.4% of individuals with mutations are asymptomatic.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected and/or has a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder or the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for typically adult-onset conditions such as BSCL2-related neurologic disorders are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers in North America would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate. In Europe and other parts of the world, prenatal diagnosis may be discouraged if treatment is not available.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information 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 Databases

Data 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)

270685SPASTIC PARAPLEGIA 17, AUTOSOMAL DOMINANT; SPG17
600794NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE VA; HMN5A
606158BSCL2 GENE; BSCL2

Normal 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 Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.263A>Gp.Asn88SerNM_032667​.6
NP_116056​.3
c.269C>Tp.Ser90Leu

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu V, Funalot B, Vance JM, Goldfarb LG, Fischbeck KH, Green ED. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet. 2003;72:1293–9. [PMC free article: PMC1180282] [PubMed: 12690580]
  2. Auer-Grumbach M, Loscher WN, Wagner K, Petek E, Korner E, Offenbacher H, Hartung HP. Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study. Brain. 2000;123:1612–23. [PubMed: 10908191]
  3. Auer-Grumbach M, Schlotter-Weigel B, Lochmuller H, Strobl-Wildemann G, Auer-Grumbach P, Fischer R, Offenbacher H, Zwick EB, Robl T, Hartl G, Hartung HP, Wagner K, Windpassinger C. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol. 2005;57:415–24. [PubMed: 15732094]
  4. Brugman F, Scheffer H, Schelhaas HJ, Nillesen WM, Wokke JH, van de Warrenburg BP, van den Berg LH. Seipin/BSCL2 mutation screening in sporadic adult-onset upper motor neuron syndromes. J Neurol. 2009;256:824–6. [PubMed: 19252810]
  5. Chen B, Zheng R, Luan X, Zhang W, Wang Z, Yuan Y. Clincial and pathological study of distal motor neuropathy with N88S mutation in BSCL2. Neuropathology. 2009;29:543–7. [PubMed: 19323790]
  6. Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004;74:1128–35. [PMC free article: PMC1182077] [PubMed: 15106121]
  7. Dierick I, Baets J, Irobi J, Jacobs A, De Vriendt E, Deconinck T, Merlini L, Van den Bergh P, Rasic VM, Robberecht W, Fischer D, Morales RJ, Mitrovic Z, Seeman P, Mazanec R, Kochanski A, Jordanova A, Auer-Grumbach M, Helderman-van den Enden AT, Wokke JH, Nelis E, De Jonghe P, Timmerman V. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. Brain. 2008;131:1217–27. [PubMed: 18325928]
  8. Irobi J, Van den Bergh P, Merlini L, Verellen C, Van Maldergem L, Dierick I, Verpoorten N, Jordanova A, Windpassinger C, De Vriendt E, Van Gerwen V, Auer-Grumbach M, Wagner K, Timmerman V, De Jonghe P. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain. 2004a;127:2124–30. [PubMed: 15242882]
  9. Irobi J, Van Impe K, Seeman P, Jordanova A, Dierick I, Verpoorten N, Michalik A, De Vriendt E, Jacobs A, Van Gerwen V, Vennekens K, Mazanec R, Tournev I, Hilton-Jones D, Talbot K, Kremensky I, Van Den Bosch L, Robberecht W, Van Vandekerckhove J, Broeckhoven C, Gettemans J, De Jonghe P, Timmerman V. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet. 2004b;36:597–601. [PubMed: 15122253]
  10. Ito D, Suzuki N. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann Neurol. 2007;61:237–50. [PubMed: 17387721]
  11. Ito D, Suzuki N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain. 2009;132:8–15. [PubMed: 18790819]
  12. Luigetti M, Fabrizi GM, Madia F, Ferrarini M, Conte A, Delgrande A, Tonali PA, Sabatelli M. Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs. Muscle Nerve. 2010;42:448–51. [PubMed: 20806400]
  13. Patel H, Hart PE, Warner TT, Houlston RS, Patton MA, Jeffery S, Crosby AH. The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12-q14, with evidence for genetic heterogeneity within this subtype. Am J Hum Genet. 2001;69:209–15. [PMC free article: PMC1226036] [PubMed: 11389484]
  14. Scarano V, Mancini P, Criscuolo C, De Michele G, Rinaldi C, Tucci T, Tessa A, Santorelli FM, Perretti A, Santoro L, Filla A. The R495W mutation in SPG3A causes spastic paraplegia associated with axonal neuropathy. J Neurol. 2005;252:901–3. [PubMed: 15742100]
  15. Silver JR. Familial spastic paraplegia with amyotrophy of the hands. Ann Hum Genet. 1966;30:69–75. [PubMed: 5964029]
  16. Yagi T, Ito D, Nihei Y, Ishihara T, Suzuki N. N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress. Hum Mol Genet. 2011;20:3831–40. [PubMed: 21750110]
  17. Windpassinger C, Wagner K, Petek E, Fischer R, Auer-Grumbach M. Refinement of the Silver syndrome locus on chromosome 11q12-q14 in four families and exclusion of eight candidate genes. Hum Genet. 2003;114:99–109. [PubMed: 13680364]

Chapter Notes

Author History

Michaela Auer-Grumbach, MD; Medical University Graz (2005-2009)
Daisuke Ito, MD, PhD (2009-present)
Klaus Wagner, MD, PhD; Medical University Graz (2005-2009)

Revision History

  • 7 June 2012 (cd) Revision: targeted mutation analysis no longer offered clinically
  • 15 September 2011 (me) Comprehensive update posted live
  • 3 September 2009 (me) Comprehensive update posted live
  • 6 December 2005 (me) Review posted to live Web site
  • 2 February 2005 (kw) Original submission
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