X-Linked Hereditary Motor Sensory Neuropathy Type 1 (CMTX1) in a Three-Generation Gelao Chinese Family.

In this report, we describe a three-generation family (the Gelao nationality, a minority ethnic group from Guizhou Province in the southwest China) with one affected member with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) in each generation. The three affected members carrying the R164W mutation in the Cx32 gene had different clinical symptoms. The proband, a 13-year-old boy presented recurrent episodes of transient central nervous system symptoms and concomitant transient diffuse white matter lesions on magnetic resonance imaging. His grandfather had the peripheral neurological presentations with later onset in the fourth decade, characterized by slowly progressive weakness of the distal muscles, atrophy, and foot deformities. But no sensory loss was observed. The proband's 38-year-old mother denied any neurological symptoms. The examination was normal except for pes cavus and diminished deep tendon reflexes in her lower limbs bilaterally. Genetic sequencing revealed the proband and his grandfather had a hemizygous mutation (p.164R > W) of CJB1 gene, and his mother had R164W heterozygous mutation. Our three cases denied symptoms of sensory disturbances, the sensory examination including touch, pin prick, and temperature sensation showed no obvious abnormalities. Thus, further investigation is needed to improve our understanding of the Cx32 protein function in the nervous system.

Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4.

Charcot-Marie-Tooth disease is a genetically heterogeneous group of motor and sensory neuropathies associated with mutations in more than 30 genes. Charcot-Marie-Tooth disease type 4J (OMIM 611228) is a recessive, potentially severe form of the disease caused by mutations of the lipid phosphatase FIG4. We provide a more complete view of the features of this disorder by describing 11 previously unreported patients with Charcot-Marie-Tooth disease type 4J. Three patients were identified from a small cohort selected for screening because of their early onset disease and progressive proximal as well as distal weakness. Eight patients were identified by large-scale exon sequencing of an unselected group of 4000 patients with Charcot-Marie-Tooth disease. In addition, 34 new FIG4 variants were detected. Ten of the new CMT4J cases have the compound heterozygous genotype FIG4(I41T/null) described in the original four families, while one has the novel genotype FIG4(L17P/nul)(l). The population frequency of the I41T allele was found to be 0.001 by genotyping 5769 Northern European controls. Thirty four new variants of FIG4 were identified. The severity of Charcot-Marie-Tooth disease type 4J ranges from mild clinical signs to severe disability requiring the use of a wheelchair. Both mild and severe forms have been seen in patients with the same genotype. The results demonstrate that Charcot-Marie-Tooth disease type 4J is characterized by highly variable onset and severity, proximal as well as distal and asymmetric muscle weakness, electromyography demonstrating denervation in proximal and distal muscles, and frequent progression to severe amyotrophy. FIG4 mutations should be considered in Charcot-Marie-Tooth patients with these characteristics, especially if found in combination with sporadic or recessive inheritance, childhood onset and a phase of rapid progression.

Charcot-Marie-Tooth disease and the cavovarus foot.

This article focuses on the cavovarus foot shape, with particular emphasis on those patients who have Charcot-Marie-Tooth disease. Recent greater understanding of this deformity has led to a better appreciation of how the underlying condition drives deformity progression and treatment of the problems associated with it. The basic science underpinning the development of Charcot-Marie-Tooth disease is reviewed and some elements of the importance of the genetic variability are emphasized. The mechanics of the development of the cavovarus foot deformity in patients who have this neuromuscular condition are reviewed and the evaluation of such patients is described. The surgical options for treatment are reviewed and the outcomes of studies relevant to surgical planning for this patient population are summarized.

Peripheral neuropathy: the importance of history and examination for correct diagnosis.

A 48-year-old woman presented to the emergency department with hematemesis and a 6-month history of unsteady gait and falls due to tripping. Because of a history of alcohol abuse, the initial diagnosis was upper gastrointestinal bleeding secondary to alcoholic gastritis or gastric ulcer, with the neuropathy likely due to alcoholism or chronic inflammatory demyelinating polyneuropathy. After further neurological examination and careful review of nerve conduction studies, however, an inherited neuropathy was suspected. Despite denial by the patient and her daughter of a family history of neuropathy, both had a pes cavus deformity with muscle atrophy and partial foot drop gait. Subsequent testing of the daughter revealed the same nerve conduction findings as the patient's. Genetic testing showed that both women had the myelin PMP22 repeat defect characteristic of Charcot-Marie-Tooth disease. Endoscopy revealed that the patient had Osler-Weber-Rendu disease, which accounted for the hematemesis.

New insights into the pathophysiology of pes cavus in Charcot-Marie-Tooth disease type 1A duplication.

Forefoot pes cavus is a cardinal sign of Charcot-Marie-Tooth disease (CMT). This review is focused on the pathophysiology of pes cavus in CMT1A duplication, which is the most common subtype of the disease. Assessment of foot deformities in CMT1A, their prevalence and proposed mechanisms, and recent contributions of magnetic resonance imaging studies of lower-leg and foot musculature are revised. Special attention is given to papers on foot deformities at initial stages of the disease. We conclude that pes cavus is an early and age-dependent manifestation of CMT1A duplication. Selective denervation of intrinsic foot musculature, particularly of the lumbricals, and not imbalance of lower-leg muscles, seems to be the initial mechanism causing reduced ankle flexibility and forefoot cavus deformity.

EEC syndrome sans clefting: variable clinical presentations in a family.

Ectrodactyly, ectodermal dysplasia and cleft palate/lip syndrome (EEC) is a rare autosomal dominant syndrome with varied presentation and is actually a multiple congenital anomaly syndrome leading to intra- and interfamilial differences in severity because of its variable expression and reduced penetrance. The cardinal features include ectrodactyly, sparse, wiry, hypopigmented hair, peg-shaped teeth with defective enamel and cleft palate/lip. A family comprising father, daughter and son presented to us with split hand-split foot deformity (ectrodactyly), epiphora, hair changes and deafness with variable involvement in each family member.

[Deletion of 17p11.2 chromosome in Spanish families with hereditary neuropathy and abnormal sensitivity to pressure]. / Deleción del cromosoma 17p11.2 en familias españolas con neuropatía hereditaria por vulnerabilidad excesiva a la presión.

Hereditary neuropathy with abnormal liability to pressure palsies (HNPP) is a dominant autosomally transmitted disease that gives rise to foci of peripheral nerve myelination, reducing conduction and leading to episodes of palsy and sensory changes that are all linked to sensitivity to pressure and traction on the affected nerve roots. The molecular basis of HNPP has been identified as a submicroscopic deletion of the 17p11.2 chromosome in exactly the same region that it is duplicated in Charcot-Marie-Tooth disease, type 1A (CMT1A). We report genetic analyses of 13 patients (belonging to 3 families) diagnosed of HNPP by means of physical examination and electrophysiologic and morphologic tests (the last in 3 cases only). Inter- and intrafamilial variation in symptomatology was studied. Some patients presented the usual clinical signs, such as recidivating brachial plexus palsy, permanent sensory polyneuropathy, foot deformities and others that might also be found in patients with CMT1A. All the patients showed electrophysiologic signs of underlying demyelinating polyneuropathy. Genetic study centered on detecting the deletion of 17p11.2 by segregation analysis with the polymorphic markers VAW409R3a (D17S122) and EW401HE (D17S61). Our results confirmed deletion at the CTM1A location of chromosome 17p11.2 in all 13 patients examined. These data suggest that the deletion of 17p11.2 plays a causal role in HNPP and that it is the most prevalent mutation in this disease; our findings constitute new evidence of the importance of the CMT1A/HNPP locus in the formation and control of peripheral myelin and in the ultimate functioning of peripheral nerves.

Oto-palato-digital syndrome type II. Report of two related cases.

Two cases with major features of bowed long bones, hypertelorism, mandibular hypoplasia and hand and foot abnormalities with early neonatal death due to respiratory failure are presented. The radiologic and clinical findings are in keeping with oto-palato-digital syndrome type II and differ significantly from other causes of bowed long bones such as campomelic and kyphomelic dysplasias.

[Charcot-Marie-Tooth syndrome. Clinico-genetic correlation in an affected family]. / Charcot-Marie-Tooth-Syndrom. Klinisch-genetische Korrelation in einer betroffenen Familie.

Hereditary motor and sensory neuropathy (HMSN) is one of the most frequently inherited causes of peripheral neurological disability. To date, the classification has been based on clinical, histological and genetic grounds. Due to increased genetic knowledge at the molecular level in recent years, diagnosis of the different subtypes has been considerably improved and their relationship clarified. We describe three generations of a family with HMSN IA (Charcot-Marie-Tooth disease IA = CMT 1A) with a genetic defect mapped to chromosome 17 and show the importance of genetic testing. Even in benign and clinically non-manifested causes of the disease, an early and non-invasive diagnosis should be made by genetic testing to identify affected persons; thus, nerve biopsy can be abandoned. Operations of pes cavus, which are not indicated and are often complicated by delayed healing, may be avoided. Instead, patients should undergo early physiotherapy and be counselled about their professional careers and family planning.