Absence of linkage of hereditary motor and sensory neuropathy type I to chromosome 1 markers

Although one large family with hereditary motor and sensory neuropathy (HMSN) type I that showed linkage to the Duffy blood group (FY) on chromosome 1 has previously been reported, we have failed to find evidence for such linkage after examining 14 markers from chromosome 1 in 12 pedigrees. We have excluded linkage between HMSN I and FY up to theta = 0.15 (lod = -3.01) and also between HMSN I and markers flanking FY; amylase (AMY), polymorphic urinary mucin (PUM), serum amyloid protein (APCS), and alpha-spectrin (SPTA). We have excluded HMSN I from 70 cM around this linkage group. Other markers examined were MS1, oncogene L-myc (MYCL), beta-subunit of nerve growth factor (NGFB), oncogene N-ras (NRAS), glucocerebrosidase (GBA), apolipoprotein AII (APOA2), antithrombin III (AT3), renin (REN), and MS32. These cover both the long and the short arms of chromosome 1 in addition to the centromeric region and yielded no evidence of linkage to HMSN I. Two-point lod scores between these markers are also presented. It is possible that there are two or more loci for HMSN I and it will be necessary to obtain significant lod scores from individual families to resolve this issue. This is increasingly possible now that hypervariable genetic markers such as PUM are available.     

Study of the duplication of 17p11.2-12 chromosome region in the patients with hereditary motor and sensory neuropathy type 1A

Charcot-Marie-Tooth neuropathy (CMT) is one of the most common hereditary disorders, affecting 1:2500 individuals. CMT is a heterogeneous group of disorders characterized by chronic peripheral motor and sensory neuropathy. We have performed the detection of 1.5 Mb CMT1A tandem duplication in 17p11.2-12 chromosome region for autosome-dominant CMT1 patients and their relatives using the analysis of two (CA)n polymorphic microsatellite loci: 17S921 and 17S1358 localised in the duplication region. CMT1A duplication was found in three of five autosome-dominant CMT1 families. It has been shown that CMT1A duplication analysis is important for early differential diagnosis of CMT including prenatal diagnosis and genetic consulting in high risk families.     

Genetic linkage and heterogeneity in type I Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy type I).

The segregation patterns of DNA markers from the pericentromeric regions of chromosomes 1 and 17 were studied in seven pedigrees segregating an autosomal dominant gene for Charcot-Marie-Tooth neuropathy type I (CMT I; hereditary motor and sensory neuropathy I). A multilocus analysis with four markers (pMCR-3, pMUC10, FY, and pMLAJ1) spanning the pericentromeric region of chromosome 1 excluded the CMT I gene from this region in six pedigrees but gave some evidence for linkage to the region of Duffy in one pedigree. Linkage of the CMT I gene to markers in the pericentromeric region of chromosome 17 (markers pA10-41, pEW301, p3.6, and pTH17.19) was established; however, in these seven pedigrees homogeneity analysis with chromosome 17 markers detected significant genetic heterogeneity. This analysis suggested that three of the seven pedigrees are not linked to this same region. Overall, two of the seven CMT I pedigrees were not linked to markers tested from chromosomes 1 or 17. These results confirm genetic heterogeneity in CMT I and implicate the existence of a third autosomal locus, in addition to a locus on chromosome 17, and a probable locus on chromosome 1. This evidence of etiological heterogeneity, supported by statistical tests, will have to be taken into consideration when fine-structure genetic maps of the regions around CMT I are constructed.     

A gene for distal arthrogryposis type I maps to the pericentromeric region of chromosome 9.

Club foot is one of the most common human congenital malformations. Distal arthrogryposis type I (DA-1) is a frequent cause of dominantly inherited club foot. Performing a genomewide search using short tandem repeat (STR) polymorphisms, we have mapped a DA-1 gene to the pericentromeric region of chromosome 9 in a large kindred. Linkage analysis has generated a positive lod score of 5.90 at theta = 0, with the marker GS-4. Multiple recombinants bracketing the region have been identified. Analysis of an additional family demonstrated no linkage to the same locus, indicating likely locus heterogeneity. Of the autosomal congenital contracture disorders causing positional foot deformities, this is the first to be mapped.     

Molecular pathogenesis of hereditary motor and sensory neuropathy

Charcot-Marie-Tooth disease 2 is an inherited axonal motor and sensory neuropathy. It is very heterogenous, both clinically and genetically. Till present, 15 types of CMT2, 14 loci and 13 genes are known to be causative of CMT2. Studying mechanisms of molecular pathogenesis is very important for finding a therapy for patients but the diversity of proteins involved in pathogenesis makes this very difficult. Proteins involved in molecular pathogenesis are e.g. proteins of the mitochondrial outer membrane with opposite functions (mitofusin 2 and GDAP1) responsible for fusion and fission of the mitochondrial network. Mutations also occur in genes encoding tRNA-synthetases, neuronal cytoskeletal protein, cation channel protein and molecular chaperones. This review presents knowledge of CMT2 and possible pathogenetic mechanisms responsible for the disease.     

Linkage analysis of neurofibromatosis type I, using chromosome 17 DNA markers.

The gene for von Recklinghausen neurofibromatosis type 1 (NF1) has recently been mapped to the pericentromeric region of human chromosome 17. To further localize the NF1 gene, linkage analysis using chromosome 17 DNA markers was performed on 11 multigeneration families with 175 individuals, 57 of whom were affected. The markers used were D17Z1 (p17H8), D17S58 (EW301), D17S54 (EW203), D17S57 (EW206), D17S73 (EW207), CRI-L946, HOX-2, and growth hormone. Tight linkage was found between NF1 and D17Z1, D17S58, and D17S57 with a recombination fraction of zero. One recombinant was detected between NF1 and D17S73, showing linkage with a 10% recombination fraction. No linkage was detected between NF1 and CRI-L946 or between HOX-2 and growth hormone. Our data are consistent with the proposed gene order pter D17S58-D17Z1-NF1-D17S57-D17S73 qter.     

Hereditary sensory neuropathy type I

Background

Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disease subdivided into three phenotypes of increasing severity: Scheie, Hurler-Scheie and Hurler. To gauge the effectiveness of treatments and to determine the load likely to fall on health-care systems, it is necessary to understand the prevalence and natural progression of the disease especially with regard to life-expectancy. In general such data on the natural history of lysosomal storage diseases is sparse.

Methods

Analysis of prevalence and patient survival in MPS I disease using a unique longitudinal data set initiated and maintained over a period of more than 20 years by the Society for Mucopolysaccharide Diseases (UK).

Results

The birth prevalence of MPS I in England and Wales over the period 1981 to 2003 was 1.07/100,000 births and within ± 5% of estimates reported in several studies that examined reasonably large populations. The median survival for MPS I patients (including all phenotypes irrespective of various treatments) was found by Kaplan-Meier analysis to be 11.6 years. This result was driven by the relatively poor survival of patients with the Hurler phenotype who, irrespective of any treatments received, had a median survival of 8.7 years; when censoring for receipt of bone marrow transplant (BMT) was implemented median survival of Hurler patients was diminished to 6.8 years. The difference between these survival curves was statistically significant by log rank test and can be attributed to beneficial effects of BMT and or selection of patients with superior prognosis for intervention with BMT. Survival curves for Hurler patients who received and did not receive BMT were very different. Probability of survival at 2 year after BMT was ~68% and was similar to this after 5 years (66%) and ten years (64%); the mean age of Hurler patients at receipt of BMT was 1.33 years (range 0.1 to 3 years). Follow up was insufficient to determine median survival of the milder phenotypes however, unsurprisingly, this was clearly superior to that for Hurler patients.

Conclusion

The birth prevalence of MPS I in England and Wales is 1.07/100,000 and the median survival for MPS I patients is 11.6 years.     

Genetics of hereditary motor and sensory neuropathy and the Costa Rican contribution

Hereditary motor and sensory neuropathy (HMSN) or Charcot-Marie-Tooth disease (CMT) is the most common hereditary illness of the peripheral nervous system. The genetics and the physiopathological aspects of the disease clarified until know, are here summarized. More than twenty genes and ten additional loci have been related with HMSN. These findings contribute to understand the metabolism of peripheral nerves and give the basis for molecular diagnostics and future therapy. Several Costa Rican families with CMT have been identified, specially with axonal forms. Two families present mutations in the myelin protein zero gene (IMPZ). In addition, linkage have been found between the disease and locus 19q13.3 in an extended family, and a mutation segregating with the disease is present in a candidate gene of the critical interval. Costa Rica has several advantages for genetical studies, that can contribute importantly in the generation of knowledge in the neurogenetical field.     

Linkage relationships of the Wiskott-Aldrich syndrome to 10 loci in the pericentromeric region of the human X chromosome

Twelve families with Wiskott-Aldrich syndrome (WAS) were studied by linkage analysis using 10 polymorphic marker loci from the X-chromosome pericentromeric region. The results confirm close linkage of WAS to the DXS14, DXS7, TIMP, and DXZ1 loci and are consistent with previous data suggesting that WAS maps to the proximal Xp and is flanked by the DXS14 and DXS7 loci. The strongest linkage (Z = 10.19 at theta = 0.00) was found to be between WAS and the hypervariable DXS255 locus, a marker locus already mapped between DXS7 and DXS14 and which was informative for all meioses included in this analysis. Linkage of the WAS to two pericentromeric Xq loci, DXS1 and PGK1, was also established. On the basis of these results, accurate predictive testing should now be feasible in the majority of WAS families.     

On the occurrence of BBB syndrome and hereditary sensory motor neuropathy in the same family.

We report the occurrence of the BBB syndrome and type 1 hereditary sensorimotor neuropathy (HSMN) in the same family: both disorders concurred in two brothers and a third presented only type 1 HSMN. The clinical findings in this family support the idea that the BBB and the G syndromes are variable manifestations of the same entity. The hypothesis that the BBB syndrome and type 1 HSMN might represent a contiguous gene syndrome is, however, not fully supported.     

Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I

Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.     

Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I

Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders.     

Molecular evolution of the human chromosome 15 pericentromeric region

We present a detailed molecular evolutionary analysis of 1.2 Mb from the pericentromeric region of human 15q11. Sequence analysis indicates the region has been subject to extensive interchromosomal and intrachromosomal duplications during primate evolution. Comparative FISH analyses among non-human primates show remarkable quantitative and qualitative differences in the organization and duplication history of this region - including lineage-specific deletions and duplication expansions. Phylogenetic and comparative analyses reveal that the region is composed of at least 24 distinct segmental duplications or duplicons that have populated the pericentromeric regions of the human genome over the last 40 million years of human evolution. The value of combining both cytogenetic and experimental data in understanding the complex forces which have shaped these regions is discussed.     

Genetic linkage mapping of multiple epiphyseal dysplasia to the pericentromeric region of chromosome 19.

Multiple epiphyseal dysplasia (MED) is an inherited chondrodystrophy that results in deformity of articular surfaces and in subsequent degenerative joint disease. The disease is inherited as an autosomal dominant trait with high penetrance. An MED mutation has been mapped by genetic linkage analysis of DNA polymorphisms in a single large pedigree. Close linkage of MED to 130 tested chromosomal markers was ruled out by discordant inheritance patterns. However, strong evidence for linkage of MED to markers in the pericentromeric region of chromosome 19 was obtained. The most closely linked marker was D19S215, with a maximum LOD score of 6.37 at theta = .05. Multipoint linkage analysis indicated that MED is located between D19S212 and D19S215, a map interval of 1.7 cM. Discovery of the map location of MED in this family will facilitate identification of the mutant gene. The closely linked DNA polymorphisms will also provide the means to determine whether other inherited chondrodystrophies have underlying defects in the same gene.     

A new variety of hereditary sensory neuropathy

Summary A pedigree with a new form of hereditary sensory neuropathy is described. Ataxia and scoliosis rather than loss of pain and ulcerating acropathy are the principal clinical features. Analysis of the pedigree suggests a dominant mode of transmission with variable age of onset and perhaps reduced penetrance.     

Ordering of markers in the pericentromeric region of chromosome 10

Seven polymorphic cosmids previously assigned to 10cen-q11.2 were mapped between D10S34 and RBP3, and ordered by interphase in situ hybridization and yeast artificial chromosome analysis. Some of the presumed unique sequences from the centromeric region have homologies either within the same region or within the centromeric region of other chromosomes.     

Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C.

Niemann-Pick type II disease is a severe disorder characterized by accumulation of tissue cholesterol and sphingomyelin and by progressive degeneration of the nervous system. This disease has two clinically similar subtypes, type C (NPC) and type D (NPD). NPC is clinically variable and has been identified in many ethnic groups. NPD, on the other hand, has been reported only in descendants of an Acadian couple who lived in Nova Scotia in the early 18th century and has a more homogeneous expression resembling that of less severely affected NPC patients. Despite biochemical differences, it has not been established whether NPC and NPD are allelic variants of the same disease. We report here that NPD is tightly linked (recombination fraction .00; maximum LOD score 4.50) to a microsatellite marker, D18S480, from the centromeric region of chromosome 18q. Carstea et al. have reported that the NPC gene maps to this same site; therefore we suggest that NPC and NPD likely result from mutations in the same gene.     

MFN2 gene analysis in patients with hereditary motor and sensory neuropathy from Bashkortostan Republic

Hereditary motor and sensory neuropathy (HMSN) type IIA is caused by mutations in the mitofusin type-2 (MFN2) gene and represents one of the most common axonal forms of HMSN. We determined the spectrum and frequency of MFN2 gene mutations in patients from the Bashkortostan Republic (BR). Four different mutations were revealed in 5 out of 170 unrelated patients, i.e., c.2113G>A (p.Val705Ile) (1.2% among all types of HMSN in the total sample of patients and 2% among patients of Tatar ethnicity). This mutation was described previously; c.775C>T (p.Arg259Cys) (0.6%, in the total sample of patients and 2% among the patients of Tatar ethnicity); c.776G>A (p.Arg259His) (0.6% in the total sample of patients and 1.5% among the patients of Russians ethnicity); and c.2171T>C (p.Leu724Pro) (1.2% in the total sample of patients and 7.4% among the patients of Bashkirs ethnicity). These are new mutations that were not observed among healthy family members and in control samples of healthy subjects. Five identified nucleotide substitutions represent single nucleotide polymorphisms of the gene, including c.892G>A (p.Gly298Arg), c.957C>T (Gly319Gly), and c1039-222t>c, which were described previously, while c.175+28c>t and c.2204+15t>c represent new nucleotide substitutions in the intron regions of the gene.