A.A.W.M. Gabreëls-Festen

Mutations in GDAP1 - Autosomal recessive CMT with demyelination and axonopathy

Background: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot–Marie–Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis. Methods: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1. Results: A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C). Conclusions: Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.

Intermediate CAG repeat lengths (53,54) for MJD/SCA3 are associated with an abnormal phenotype

We report on a Dutch family in which 4 members in 2 generations have intermediate repeat lengths (53 and 54) for Machado‐Joseph Disease/ Spinocerebellar Ataxia (MJD/SCA3). All but the youngest have a restless legs syndrome with fasciculations and a sensorimotor axonal polyneuropathy. Central neurological abnormalities are only present in 2. This family shows that intermediate repeat lengths can be pathogenic and may predispose for restless legs and peripheral nerve disorder.

Transient cerebral white matter lesions in a patient with connexin 32 missense mutation

X-linked dominant Charcot-Marie-Tooth disease (CMT1X) is an inherited motor and sensory neuropathy that is associated with mutations in the gap junction protein connexin 32. Several authors have reported CNS involvement with1-2⇓ and without3-4⇓ cerebral abnormalities on MRI. We present a patient who developed subacute respiratory distress and a pseudobulbar syndrome after an episode of fever. MRI of the brain showed confluent cerebral white matter lesions. The clinical features and cerebral white matter lesions resolved spontaneously.nnA 14-year-old boy presented with gait difficulties and weakness in both feet. His symptoms had insidiously started 10 years previously. There was no history of recent immunization, and he did not use any drugs. Family history revealed that the patient’s mother from an early age had the same foot deformities as her son; …

Phenotype of Charcot–Marie–Tooth disease Type 2

Objective: To investigate the clinical and electrophysiologic phenotype of Charcot–Marie–Tooth disease (CMT) Type 2 in a large number of affected families. Methods: We excluded CMT Type 1, hereditary neuropathy with liability to pressure palsies, and CMT due to Cx32 gene mutations by DNA analysis. We performed genetic analysis of the presently known CMT Type 2 genes. Results: Sixty-one persons from 18 families were affected. Ninety percent of patients were able to walk with or without the help of aids. Proximal leg muscle weakness was present in 13%. Asymmetrical features were present in 15%. Normal or brisk knee reflexes were present in 36%. Extensor plantar responses without associated spasticity occurred in 10 patients from eight families. Only three causative mutations were identified in the MFN2, BSCL2, and RAB7 genes. No mutations were found in the NEFL, HSPB1, HSPB8, GARS, DNM2, and GDAP1 genes. Conclusions: At group level, the clinical phenotype of Charcot–Marie–Tooth disease (CMT) Type 2 is uniform, with symmetric, distal weakness, atrophy and sensory disturbances, more pronounced in the legs than in the arms, notwithstanding the genetic heterogeneity. Brisk reflexes, extensor plantar responses, and asymmetrical muscle involvement can be considered part of the CMT Type 2 phenotype. The causative gene mutation was found in only 17% of the families we studied.

Mononeuropathy multiplex as the initial manifestation of neurofibromatosis type 2

The authors report a patient with neurofibromatosis type 2 (NF2) presenting with an axonal mononeuropathy multiplex. Sural nerve biopsy showed small scattered groups of Schwann cells transformed into irregular branching cells with abnormal cell—cell contacts. The authors hypothesize that defective Schwann cell function, due to inactivation of the NF2 gene product merlin, leads to changes in morphology, cell–cell contact, and growth, and finally to degeneration of axons.

Axon damage in CMT due to mutation in myelin protein P0.

We describe a family carrying the Thr148Met mutation in the P0 gene. Contrary to other neuropathies caused by myelin gene defects, no demyeliantion could be found in our biopsies. Based on follow up examinations, extensive morphometry and immunohistochemical analysis we suggest that the mild hypomyelination documented in our family secondarily causes axonal degeneration and axonal loss of large and small fibers which predominates the clinical picture.

Cerebrotendinous xanthomatosis: Controversies about nerve and muscle: observations in ten patients

Neuromuscular characteristics were documented in ten patients with biochemically and genetically confirmed cerebrotendinous xanthomatosis. An array of genotypes was found in these patients. Only one patient complained of muscle weakness, while clinical signs of peripheral neuropathy were present in six patients. Electromyogram showed predominantly axonal neuropathy in seven patients. Neurogenic changes were seen in muscle biopsies of nine patients. Sural nerve biopsies of three patients showed features of axonal neuropathy. In addition, in one patient, extensive onion bulb formation was seen, which is indicative of a primarily demyelinating process. Five patients had normal mitochondrial respiratory chain enzyme activity. It is concluded that myopathy is not a feature of cerebrotendinous xanthomatosis and that the most prominent neuromuscular abnormality is sensorimotor axonal polyneuropathy.

Histology of hereditary neuralgic amyotrophy

We report the findings in five muscle and three sural nerve biopsies, and in one postmortem plexus specimen, from six patients with hereditary neuralgic amyotrophy (HNA). We found that the sensory nerves are definitely involved in HNA despite the mainly motor symptoms, and that lesions in nerves and muscles are more widespread throughout the peripheral nervous system than clinically presumed, but, simultaneously, very focally affect isolated fascicles within individual nerves.

Sensorineural hearing impairment in patients with Pmp22 duplication, deletion, and frameshift mutations.

Objective: To characterize and distinguish the types of sensorineural hearing impairment (SNHI) that occur in hereditary motor and sensory neuropathy Type 1a (HMSN-1a) and hereditary neuropathy with liability to pressure palsies (HNPP), which are caused by deletion or frameshift mutation. Study Design: Prospective study. Setting: Ambulatory patients in a university hospital. Patients: Twelve patients with HMSN-1a due to a duplication of the PMP22 gene on chromosome 17p11.2, 16 patients with HNPP due to the common PMP22 deletion (HNPP del), and 11 HNPP patients with a frame shift mutation (heterozygous PMP22 G-insertion) (HNPP mut), all confirmed by molecular genetic analysis. Interventions: Pure-tone audiograms and speech audiograms were obtained. Main Outcome Measures: Results of cross-sectional analysis comprising linear regression of hearing threshold on age. Results: Pure-tone audiograms showed mild to moderate SNHI, predominant at the low and the high frequencies. SNHI showed significant progression by approximately 0.4 dB per year at 0.25 to 4 kHz and up to 1 to 2 dB per year at 4 to 8 kHz. Patients with HMSN-1a had substantial, presumably congenital, SNHI but did not show significant progression beyond presbyacusis. Patients with HNPP showed postnatal onset at age 11 years with progression of SNHI in excess of presbyacusis by 0.4 dB per year. All three types of neuropathy showed normal speech recognition. Conclusions: All three types of neuropathy showed SNHI with normal speech recognition. HMSN-1a showed stable SNHI without progression beyond presbyacusis. HNPP showed progression beyond presbyacusis with postnatal onset. The differences in SNHI may be explained by the differences in PMP22 expression. The progressive SNHI in HNPP might be explained by the liability for exogenous factors associated with this disorder.

Neurophysiologic studies in early-onset cerebellar ataxia

Summary: The discovery of the gene for Friedreichs ataxia (FRDA) has not only broadened the FRDA phenotype, but has also identified patients with early-onset cerebellar ataxia who resemble FRDA clinically but who do not carry a mutation in the frataxin gene. In order to identify subgroups that may represent a uniform underlying disorder, we performed neurophysiologic studies, including nerve conduction studies, electromyography, and transcranial magnetic stimulation, in 15 patients with a slowly progressive, unexplained, early-onset cerebellar ataxia (EOCA). In addition, sural nerve biopsy data were available in four patients. The neurophysiologic data identified three distinctive groups of EOCA patients: three patients with normal motor and sensory conduction velocities and borderline sensory amplitudes (group 1); three patients with a mild, predominantly motor, axonal neuropathy (group 2); and nine patients with a highly uniform syndrome characterized by pyramidal features and a severe sensory and motor axonal neuropathy (group 3). We conclude that, on the basis of neurophysiologic studies, distinctive groups of patients with EOCA can be delineated, and that differentiation between patients with EOCA can be useful for differential diagnostic consideration. Whether this splitting also reflects a fundamental phenotypic difference and, therefore, may direct future DNA studies, remains to be established.