Ulcero-mutilating neuropathy in an Austrian kinship without linkage to hereditary motor and sensory neuropathy IIB and hereditary sensory neuropathy I loci

OBJECTIVE: To elucidate genetic heterogeneity in ulcero-mutilating neuropathy. BACKGROUND: Ulcero-mutilating features and sensory loss have been observed in hereditary sensory neuropathy (HSN) and hereditary motor and sensory neuropathy (HMSN). HSN is characterized by marked distal sensory loss, frequent toe and foot ulcerations, osteomyelitis, and necrosis, which may be complicated by toe or limb amputations. Motor and autonomic nerve involvement can also occur to a variable degree. Recently, autosomal-dominant HSN type I was mapped to chromosome 9q22 in four families. In two other families with ulcero-mutilating neuropathy, a gene locus was assigned to chromosome 3q13-q22. Because motor symptoms were prominent in these latter two kinships, the disease was designated HMSN type IIB or Charcot-Marie-Tooth type 2B (CMT2B) neuropathy. METHODS: We report detailed clinical, electrophysiologic, and genetic data on a large Austrian family with ulcero-mutilating neuropathy, sensory loss, and amputations. RESULTS: Linkage analysis with chromosomal markers representing the HSN I and HMSN IIB loci excluded these gene loci in our family. CONCLUSIONS: These findings therefore indicate the existence of a third gene locus in autosomal-dominant inherited ulcero-mutilating neuropathies, showing that these neuropathies are genetically highly heterogeneous.     

A family with autosomal dominant mutilating neuropathy not linked to either Charcot-Marie-Tooth disease type 2B (CMT2B) or hereditary sensory neuropathy type I (HSN I) loci.

Sensory loss and ulcero-mutilating features have been observed in hereditary sensory neuropathy type I and in hereditary motor and sensory neuropathy type IIB, also referred as Charcot-Marie-Tooth disease type 2B. To date two loci associated with ulcero-mutilating neuropathy have been described: CMT2B at 3q13-q22 and HSN I at 9q22.1-q22.3. We performed linkage analysis with chromosomal markers representing the hereditary sensory neuropathy type I and Charcot-Marie-Tooth disease type 2B loci on an Italian family with a severe distal sensory loss leading to an ulcero-mutilating peripheral neuropathy. Negative likelihood-of-odds scores excluded any evidence of linkage to both chromosome 3q13 and chromosome 9q22 markers, confirming the genetic heterogeneity of this clinical entity and the presence of a third locus responsible for ulcero-mutilating neuropathies.     

Genetic Study of Demyelinating form of Autosomal-Recessive Charcot–Marie–Tooth Diseases in a Turkish Family

Charcot–Marie–Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral motor and sensory neuropathies characterized by distal muscle weakness atrophy predominantly in the lower extremities, diminished or absent deep tendon reflexes, distal sensory loss and skeletal deformities. Mode of inheritance could be either autosomal dominant, autosomal recessive, or X-linked. The autosomal-recessive subgroup of CMT (AR-CMT) neuropathies is heterogeneous as well. To date, nine demyelinating loci have been implicated in CMT4 and seven genes have been identified. It has been screened in this study for the presence of mutations in the coding region of GDAP1 and genetic linkage analyses of CMT4B1, CMT4B2, CMT4C, CMT4D, CMT4E, and CMT4F loci were tested in a Turkish family presenting recessively inherited form of CMT disease characterized by severe motor weakness. We did not find any mutations in GDAP1 and genetic linkage excluded for the six demyelinating genes loci (CMT4B1, CMT4B2, CMT4C, CMT4D, CMT4E, and CMT4F). Our findings indicate that another locus may be associated with AR-CMT disease.     

Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family.

BACKGROUND: Charcot-Marie-Tooth disease type 2 (CMT2) or hereditary motor and sensory neuropathy type II (HMSN II) is an inherited axonal neuropathy of the peripheral nervous system. Three autosomal dominant CMT2 loci have been located on chromosomes 1p35-p36 (CMT2A), 3q13-q22 (CMT2B), and 7p14 (CMT2D) indicating that CMT2 is a genetically heterogeneous disorder. METHODS: A CMT2 family was examined for linkage to the CMT2A, CMT2B, and CMT2D loci using short tandem repeat polymorphisms. RESULTS: Suggestive evidence for linkage to 3q13-q22 was found. Recombinations occurred with markers D3S1769 and D3S1267 indicating that the CMT2B locus is located distal to D3S1267 and resides in an interval of 25 cM. Some patients in this family have pronounced sensory disturbances leading to poorly healing ulcerations. CONCLUSIONS: These unusual sensory signs for CMT were also noted in the only other CMT2B family reported so far, suggesting a distinct clinical phenotype for CMT2B. Exclusion of the locus for hereditary sensory neuropathy type I (HSN I) on chromosome 9q22 indicates that HSN I with mild motor symptoms and CMT2 with prominent sensory abnormalities are not allelic.     

SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I

Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant ulceromutilating disorder of the peripheral nervous system characterized by progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long-chain base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1 gene (c.1160G-->C; p.G387A) in twin sisters with a severe HSN I phenotype is reported.     

A novel type of hereditary motor and sensory neuropathy characterized by a mild phenotype.

BACKGROUND: Three loci for autosomal dominant hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1) have been identified on chromosomes 17p11.2 (CMT1A), 1q21-q23 (CMT1B), and 10q21.1-q22.1 (designated here as CMT1D). The genes involved are peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), and the early growth response element 2 (EGR2), respectively. Probably a fourth locus (CMT1C) exists since some autosomal dominant HMSN I families have been excluded for linkage with the CMT1A and CMT1B loci. Four loci for autosomal dominant hereditary motor and sensory neuropathy type II (HMSN II) or Charcot-Marie-Tooth disease type 2 (CMT2) have been localized on chromosomes 1p35-p36 (CMT2A), 3q13-q22 (CMT2B), 7p14 (CMT2D), and 3p (HMSN-P). OBJECTIVE: To describe the clinical, electrophysiologic, and neuropathological features of a novel type of Charcot-Marie-Tooth disease. PATIENTS AND METHODS: We performed linkage studies with anonymous DNA markers flanking the known CMT1 and CMT2 loci. Patients and their relatives underwent clinical neurologic examination and electrophysiologic testing. In the proband, a sural nerve biopsy specimen was examined. RESULTS: Linkage studies excluded all known CMT1 and CMT2 loci. The clinical phenotype is mild and almost all affected individuals remain asymptomatic. Electrophysiologic and histopathological studies showed signs of a demyelinating neuropathy, but the phenotype is unusual for either autosomal dominant HMSN I or HMSN II. CONCLUSION: Our findings indicate that the HMSN in this family represents a novel clinical and genetic entity.     

Unravelling the molecular basis of CMT4B pathology

Distal hereditary motor neuronopathy (distal HMN) is a genetically and clinically heterogeneous disorder. To date three loci have been identified on chromosomes 7p14, 9q34 and 12q24. We describe a four generation Italian family with distal HMN starting at around 30 years of age with weakness and atrophy of distal leg muscles and pyramidal features. We performed genetic linkage analysis with microsatellites on chromosomes 7p14, 9q34 and 12q24. Negative LOD scores excluded any evidence of linkage to the above‐mentioned chromosomes in the family. Moreover, because of pyramidal features in our patients, we performed the linkage analysis to all the known loci for autosomal dominant hereditary spastic paraparesis (ADHSP). The analysis was negative thus excluding that our patients were affected by a complicated form of ADHSP. These data further confirm a genetic heterogeneity within inherited motor neuronopathy disorders.     

Further evidence of genetic heterogeneity in autosomal dominant distal motor neuronopathy

Distal hereditary motor neuronopathy is a genetically and clinically heterogeneous disorder. To date, five loci, and their relative genes, have been mapped on chromosomes 7p14, 7q11, 9q34, 11q12 and 12q24, respectively. We describe an Italian family with autosomal dominant distal HMN starting at around 30 years of age with weakness and atrophy of distal leg muscles and pyramidal features. We performed genetic linkage analysis on chromosomes 7p14, 9q34, 11q12 and 12q24. Moreover we sequenced the genes mapped to 7q11 and 12q24. Negative LOD scores excluded linkage to 7p14, 9q34, and 11q12 chromosomes in our family. No mutations were found in genes mapped to 7q11 and 12q24. In addition, because of pyramidal features, we performed the linkage analysis to all the known loci for autosomal dominant hereditary spastic paraparesis. The analysis was negative thus excluding a complicated form of autosomal dominant hereditary spastic paraparesis. These data further confirm a genetic heterogeneity within inherited motor neuronopathy.     

Autosomal dominant burning feet syndrome

Familial burning feet syndrome inherited as an autosomal dominant trait has been described in only one family. Due to an associated sensory neuropathy the autosomal dominant burning feet syndrome was suggested to represent a variant form of hereditary sensory and autonomic neuropathy type I (HSAN I). Clinical, histopathological, and molecular genetic studies were performed in a large German kindred with autosomal dominant burning feet syndrome. The autosomal dominant burning feet syndrome was associated with a neuropathy predominantly affecting small unmyelinated nerve fibres. Linkage to the HSAN I locus on chromosome 9q22 and to the Charcot-Marie-Tooth disease type 2B (CMT 2B) locus on chromosome 3q13-q22 was excluded. The autosomal dominant burning feet syndrome is neither allelic to HSAN I nor to CMT 2B and thus represents a distinct genetic entity.     

Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.     

Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy

Recently point mutations in the SPTLC1 subunit of serine palmitoyltransferase have been shown to cause the common form of dominant hereditary sensory neuropathy (HSN1). Serine palmitoyltransferase (SPT) is a heterodimeric molecule made up of two subunits, SPTLC1 and SPTLC2. Twelve index patients from families with presumed genetic sensory neuropathies were screened for SPTLC2 mutations. These families comprised six multigenerational families, including two previously reported families not linked to the SPTLC1 locus on chromosome 9 and one multigenerational family with a complicated hereditary sensory neuropathy syndrome with associated palmar plantar keratosis, ataxia and spastic paraplegia. The remaining families included one consanguineous family with presumed recessive HSN with two affected siblings, one case of congenital sensory neuropathy and four sporadic cases with adult onset sensory neuropathy. No mutations in the SPTLC2 gene were found in any family. These results suggest that SPTLC2 mutations are not a common cause for genetic sensory neuropathies.     

The phenotypic manifestations of autosomal recessive axonal Charcot-Marie-Tooth due to a mutation in Lamin A/C gene

Charcot-Marie-Tooth disease constitutes a genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. The axonal type of Charcot-Marie-Tooth is designated type 2. Six loci for autosomal dominant and three for recessive Charcot-Marie-Tooth type 2 have been reported so far. In this study we report the phenotype of autosomal recessive axonal Charcot-Marie-Tooth type 2 due to a recently-described mutation (c.892C>T-p.R298C) in a gene encoding Lamin A/C nuclear envelope proteins and the first gene in which a mutation leads to autosomal recessive Charcot-Marie-Tooth type 2. We have explored eight patients from four Algerian families. The onset is usually in the second decade and the course is rapid, involving upper limbs and proximal muscles, leading to a severe condition in less than 4 years. Many different mutations in Lamin A/C have been identified as causing variable phenotypes, such as limb girdle muscular dystrophy type 1B, autosomal dominant and recessive Emery-Dreyfuss muscular dystrophy, dilated cardiomyopathy with atrioventricular conduction defect, and Dunnigan-type familial partial lipodystrophy should prompt us to fully investigate the skeletal and cardiac muscles in patients affected with autosomal recessive Charcot-Marie-Tooth type 2 carrying a mutation in LMNA.     

A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family

Charcot-Marie-Tooth (CMT) disease is the most-common form of inherited motor and sensory neuropathy. The autosomal dominant axonal form of the disease (CMT2) is currently subdivided into seven types based on genetic localization. These are CMT2A (1p35-p36), CMT2B (3q13-q22), CMT2C (unknown), CMT2D (7p14), CMT2E (8p21), HMNSP (3q13.1), and CMT2F (7q11-q21). Two loci have thus far been identified for autosomal recessive CMT2; ARCMT2A (1q21.1-q21.3) and ARCMT2B (19q13.3). Mutations in four genes (connexin 32, myelin protein zero, neurofilament-light, and kinesin) have been associated with the CMT2 phenotype. We identified a novel neurofilament-light missense mutation (C64T) that causes the disease in a large Slovenian CMT2 family. This novel mutation shows complete co-segregation with the dominantly inherited CMT2 phenotype in our family. Electronic Publication     

Hereditary spastic paraplegia associated with peripheral neuropathy: a distinct clinical and genetic entity

Hereditary motor and sensory neuropathy type V is a very rare disease in which hereditary spastic paraplegia is associated with peripheral motor and sensory neuropathy. The symptomatic onset of the disorder is usually in the second decade of life or later and the course is progressive over many years. Hereditary motor and sensory neuropathy type V is inherited as an autosomal dominant trait usually showing incomplete penetrance. So far, no molecular data are available in the literature about this disease. In our study we present clinical and molecular data from a large Italian family displaying hereditary motor and sensory neuropathy type V. Taking into account the clinical features in this family, we have performed a linkage analysis for markers strictly associated with all the known loci for autosomal dominant and autosomal recessive forms of hereditary spastic paraplegia and hereditary motor and sensory neuropathy type II, and have found no linkage to these loci. Our study suggests that hereditary motor and sensory neuropathy type V is not only a distinct clinical entity but also a distinct genetic entity.     

Coexistence of Charcot‐Marie‐Tooth disease type 1A and anti‐MAG neuropathy

At age 35, a man with a genetic diagnosis of Charcot‐Marie‐Tooth disease type 1A (CMT1A) but no family history of neuropathy and no clinical symptoms developed rapidly progressive loss of balance, distal limb numbness, loss of manual dexterity, and hand tremor. Five years later, he walked with support and had mild pes cavus, marked sensory ataxia, severe leg and hand weakness, absent deep tendon reflexes (DTRs), severe sensory loss, and hand tremor. He had dramatically reduced motor nerve conduction velocity (MNCV), strikingly prolonged motor distal latencies, absent sensory action potentials and lower limb compound muscle action potentials. CMT1A duplication was reconfirmed but the dramatic change in his clinical course suggested a superimposed acquired neuropathy. An IgM‐kappa monoclonal gammopathy of uncertain significance (MGUS) with high titer anti‐myelin associated glycoprotein (anti‐MAG) activity was found. Nerve biopsy showed severe loss of myelinated fibers with onion bulbs, no evidence of uncompacted myelin, and few IgM deposits. Rituximab was given and he improved. It is very likely that this is a chance association of two rare and slowly progressive neuropathies; rapidly worsening course may have been due to a “double hit”. Interestingly, there are reports of possible superimposition of dysimmune neuropathies on hereditary ones, and the influence of the immune system on inherited neuropathies is matter for debate.     

A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family

Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder clinically characterized by distal and proximal sensory loss that is caused by the reduction or absence of peripheral sensory nerves. Recently, a novel gene called HSN2 has been found to be the cause of HSAN type II in five families from Newfoundland and Quebec. Screening of this gene in an HSAN type II Lebanese family showed a 1bp deletion mutation found in a homozygous state in all affected individuals. This novel mutation supports the hypothesis that HSN2 is the causative gene for HSAN type II.     

Hereditary recurrent focal neuropathies: clinical and molecular features

The authors review the molecular genetics and pathophysiology of hereditary recurrent focal neuropathies: hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary neuralgic amyotrophy (HNA). Significant progress in the understanding of HNPP and HNA has been achieved. HNPP and HNA are distinct clinical and pathologic disease entities with autosomal dominant inheritance. Molecular genetic studies have shown that HNPP and HNA are located on chromosome 17 but at distinct genetic loci (17p11.2 for HNPP, 17q25 for HNA). The 1.5 megabase deletion in 17p11.2 is the major cause of HNPP. This interstitial deletion causes the complete loss of one allele of the peripheral myelin protein 22 (PMP22) gene. Interestingly, rare HNPP patients are found without the 1.5 megabase deletion. However, these patients have distinct mutations in the PMP22 gene resulting in altered expression of the PMP22 protein. Current molecular genetic tests and clinical guidelines allow improved diagnosis, prognosis, and genetic counseling for patients with HNPP. Such tests are not available for HNA, because the disease-causing gene remains unknown. Molecular genetic advances in HNPP and HNA, as well as the study of transgenic animal and cellular models, will provide a more precise understanding of the disease mechanisms and will lead to the development of effective therapeutic tools for patients with inherited and sporadic recurrent peripheral neuropathies.