Central motor conduction in a family with hereditary motor and sensory neuropathy with pyramidal signs (HMSN V).

Two generations of a family affected by hereditary motor and sensory neuropathy with pyramidal signs (HMSN V) were clinically and electrophysiologically examined. Apart from electroneurographic studies, the central motor conduction (CMC) to arm and leg muscles was assessed using magnetic transcranial motor cortex stimulation. Abnormal CMC was confined to the clinically affected members, with the exception of an unaffected subject who had a diminished but normal latency response in a leg. The typical pattern was a significant diminution of the compound muscle action potential from the tibialis anterior and a moderately prolonged cortico-muscular conduction time (CoMCT) to this muscle.     

Occurrence of active demyelinating lesions in children with hereditary motor and sensory neuropathy (HMSN) type I

Summary In three children with dominant hereditary motor and sensory neuropathy type I, peripheral nerve biopsy showed the classical lesions of segmental demyelination with remyelination and onion bulb formations. In two cases, ultrastructural examination also demonstrated numerous characteristic features of active demyelination. The presence of active demyelinating lesions suggests an autoimmune attack superimposed on the course of a chronic genetic disease.     

Immunological study of hereditary motor and sensory neuropathy type 1a (HMSN1a)

OBJECTIVES: Fifty three patients were studied to investigate whether autoimmune or inflammatory mechanisms could explain the phenotypic heterogeneity of patients with hereditary motor and sensory neuropathy type 1a (HMSN1a). METHODS: Serum samples were examined for antibodies to peripheral nerve myelin protein 22 (PMP22), ganglioside GM1 and cauda equina homogenate, and interleukin-6 (IL-6) and soluble tumour necrosis factor receptor 1 (sTNF R1) concentrations. Serological results were compared with those from patients with other neuropathies (ONPs, n=30) and with normal subjects (n=51). RESULTS: In the group as a whole, no relation emerged between clinical severity and any immune parameters. Immunohistochemical examination of four sural nerve biopsies did not show significant inflammatory infiltration. In a subset of 12 patients who experienced stepwise progression of disease, there was a trend towards a higher proportion having anti-PMP22 antibodies (33% v 15% of those with gradual disease progression, 3% ONPs, and no normal controls) and complement fixing antibodies to human cauda equina (25% v 5% with gradual progression, 8.6% ONPs, 3.9% normal controls, p=0.07). CONCLUSIONS: Patients with HMSN1a and a stepwise disease progression may have an inflammatory, autoimmune component superimposed on the genetic condition.     

A family of hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V)

Three siblings with hereditary motor and sensory neuropathy with spastic paraplegia (HMN V) were described. Their grandfather was suspected to have the similar symptoms. Their parents were normal and not consanguineous. The first case was a 54-year-old woman. She has suffered from difficulty in walking since the age of 10 years. Distal muscular weakness and wasting began at 20 years old. She was admitted to our hospital for investigation in 1988. Results of examination of the brain, cranial nerve, and cerebellar function were normal. The deep reflexes were hyperactive in the arm and knee, while absent at the ankle. Babinski's sign was definitely positive. Muscular weakness and wasting were noted in intrinsic hand muscles and in those below her knees. There were pes cavus and hammer toes, and the gait was spastic. Mild sensory disturbance was noted in distal limbs. The conduction velocity of motor nerve fibers of her limbs was below normal and that of sensory nerve fibers normal. Muscle biopsy of biceps brachii revealed neurogenic changes. Sural nerve biopsy showed decreased number of myelinated fibers of large diameter and formation of small oinion-bulb. The second and third cases were her brothers and proven to have the similar condition, but their onset of illness were earlier and their affections were more severe. A few cases of HMSN V with nerve biopsy findings have so far been reported and the family presented here is the first report in Japan.     

Increased systemic B- and T-lymphocyte responses in hereditary motor and sensory neuropathy (HMSN I).

Immune mechanisms of possible importance for the development and maintenance of peripheral nerve myelin breakdown in HMSN I were analysed by measuring B- and T-cell activation in blood, bone marrow and cerebrospinal fluid. Patients with polyneuropathies of other etiologies served as one control group and patients with tension headache as another. Flow cytometry of blood and bone marrow mononuclear cells revealed that an increased number of CD3+, CD4+ and CD4- CD8- T-cells expressed a late stage activation marker (Ta1). Analysis of T-cells primed for myelin antigens, by studies of IFN-gamma secretion in response to antigen in vitro, showed that both HMSN I and other polyneuropathy patients had low (but significant) numbers of T-cells recognizing whole PNS-myelin. Increased numbers of IgG- and IgM-producing cells were found in blood and bone marrow in the HMSN I patients. Patients with both HMSN I and the other polyneuropathies had few cells in peripheral blood and in bone marrow producing antibodies binding to P2, MAG and MBP in a solid phase immunospot assay. Many cells in the cerebrospinal fluid produced antibodies against MAG. Thus, there was a strong general activation of B- and T-cells in HMSN I while the immunity directed toward peripheral nerve was only slightly elevated. It is an open question if this immune activation is related to the primary gene defect or a secondary event to the nerve damage. The pathogenetic importance of the immune response in maintaining the nerve damage in HMSN I is unclear.     

Hereditary motor and sensory neuropathy (HMSN) and optic atrophy (HMSN type VI,Vizioli)

Summary Clinical and electrophysiological findings are described in three patients with hereditary motor and sensory neuropathy in association with optic atrophy (HMSN VI). The optic atrophy was of the Leber type in a 15-year-old boy. In a 70-year-old patient, as in three members of his family, optic atrophy was associated with tapetoretinal degeneration. In addition to HMSN and optic atrophy a 20-year-old man suffered from sensorineural deafness. Electrophysiological studies indicated a neuronal form of neuropathy, as in HMSN II. Brainstem auditory evoked potentials also revealed subclinical involvement of the central auditory pathways in the patients without hearing defects.Presented in part at the Working Meeting of the German Neurological Society (Arbeitstagung der Deutschen Gesellschaft für Neurologie), Essen, 24 September 1987     

Longitudinal conduction studies in hereditary motor and sensory neuropathy type 1

Motor conduction studies were performed serially in 10 patients, ages 10-62 years, with clinical and electrophysiological criteria of hereditary motor and sensory neuropathy type 1 (HMSN-1) over periods of 11-19 years. Median nerve conduction velocity (MNCV) and distal motor latency showed no significant change on serial studies. Mean median compound muscle action potential (CMAP) amplitude values, however, decreased 66% in 8 patients. Observed clinical progression in HMSN-1, over prolonged periods of time, was not associated with MNCV slowing. However, CMAP amplitude reduction, reflecting progressive axonal loss, correlated with clinical deterioration.     

Somatosensory evoked potentials,sensory nerve potentials and sensory nerve conduction in hereditary motor and sensory neuropathy type I

Summary Thirty-nine patients from six families with hereditary motor and sensory neuropathy type I and control subjects were included in this study. A neurological deficit score (NDS) was derived from a neurological examination and compared with neurophysiological test findings. Further, sensory nerve conduction velocities (SNCV) were compared with the motor nerve conduction velocities (MNCV). Five patients whom peaks of N11/N13 complex and N20 of the median nerve sensory evoked potential (SEP) could be recorded showed normal interpeak latency. The interpeak separation P14 N20 measured in six patients was normal. These findings point to the normal function of the central conductive pathways. Erb and cervical potentials of the median nerve SEP could be recorded in 10% and 12% of the patients, respectively. In contrast, about half of the patients showed a scalp N20, while in most of them no SNCV could be measured. In six patients far-field potential P14 of the median nerve SEP was the first detectable potential. Therefore, we argue in view of the anatomical structure of the thalamus, that the first generator for synchronizing and amplification of impulses is probably located in the thalamus. A third of the patients had a cortical sural nerve SEP, while no sural nerve potentials could be recorded. No association was found between the SEP findings and the NDS. There was an inverse correlation between median SNCV and the NDS, but no relationship between the former and sensory deficit alone. In 40% of the patients median SNCV and in 13% sural SNCV could be recorded and considered to be severely decreased. In contrast, the majority of the patients had mild to moderate sensory deficit. Furthermore, patients with measurable SNCVs had higher MNCVs and lower NDS than patients without measurable SNCVs.     

Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I).

Seventeen cases of dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I) with infantile onset were studied. Not only clinical and electrophysiological data, but also the g ratio (axon diameter to fibre diameter), considered to be a distinguishing feature between HMSN type I and HMSN type III, showed overlap. Morphological and morphometrical investigations already revealed a lack of small and large diameter myelinated axons at an early stage, and a demyelinating process most active in early childhood followed later by axonal loss. It was concluded that the histopathology of HMSN type I cannot be sufficiently explained by axonal atrophy with secondary demyelination.     

Detection of hereditary motor sensory neuropathy type I in childhood.

Clinical signs and slowed motor nerve conduction velocities were found in 17 of 36 children under 10 years of age who had one parent with hereditary motor sensory neuropathy type I (HMSN I). Four children had slowed conduction velocities at one year or less. Clinical signs were subtle and included pes planus, distal foot wasting, weakness of ankle eversion and dorsiflexion and areflexia. HMSN I can be detected reliably in children, even before one year of age.     

Autosomal recessive form of hereditary motor and sensory neuropathy type I.

We studied pathologic changes in sural nerve biopsies from four patients with probable autosomal recessive (AR) hereditary motor and sensory neuropathy (HMSN) type I with a median motor nerve conduction velocity greater than 10 m/sec, comparing them with the pathologic features in autosomal dominant (AD) HMSN type I. The four recessive and two sporadic cases showed segmental demyelination. However, the classic onion bulbs of concentric Schwann cell processes, which occur in AD type I, were rare; many axons, also of a smaller size, were surrounded by onion bulbs of basal laminae. Schwann cells of the myelinated and unmyelinated types were involved in these onion bulb formations. Patients with HMSN type I who have many basal lamina onion bulbs should be considered as having AR inheritance.     

Linkage analysis of Charcot-Marie-Tooth neuropathy (HMSN type I)

Fifteen HMSN families with 218 members and documented male-to-male transmission and slow motor nerve conduction velocities were informative for linkage to Duffy blood group (Fy), antithrombin III cDNA probe (AT3) and renin (REN). Our data support linkage to Fy in 8 families (lod score = 2.45 at θ = 0) consistent with HMSN type IB. Linkage to AT3 (lod score = 1.28 at θ = 0) and linkage of Fy to AT3 (lod score = 1.61 at θ = 0) is also supported in 3 of the 8 original families. Linkage to REN (lod score = 0.78 at θ = 0), linkage of Fy to REN (lod score = 0.89 at θ = 0), and linkage of AT3 to REN (lod score = 0.88 at θ = 0) is supported in only 2 of the 8 original families. Linkage to Fy was rejected in seven families, consistent with HMSN type IA (lod score = −4.34 at θ = 0.05). Linkage to AT3 was rejected in 12 families (lod score = −9.52 at θ = 0.05). Linkage to REN was rejected in 13 families (lod score = −11.07 at θ = 0.05). Our data provide support for the concept of genetic heterogeneity in CMT hypertrophic neuropathy (HMSN type I). The linkage of HMSN type IB to Fy seems to be tighter than to AT3 and REN, strongly suggesting the mapping of HMSN type IB locus on the proximal part of the long arm of chromosome 1, close to the centromere.     

The application of nerve conduction and clinical studies to genetic counseling in hereditary motor and sensory neuropathy type I

One hundred and thirty two individuals at risk for hereditary motor and sensory neuropathy (HMSN) type I from 11 unrelated families were evaluated by physical examination. Motor conduction velocity (MCV) studies of median and/or peroneal nerves were performed on 99 of them. Seventy-three subjects were found to be affected. In all age categories including the first decade of life, the ratio of affected individuals at risk did not significantly differ from the expected 1:1 ratio; that is, penetrance of the gene was complete. The majority of affected members in the first decade had no clinical features considered diagnostic of peroneal muscular atrophy syndrome, and full clinical expression developed in the second decade. Marked slowing of MCV was already present in the early years of life, even as young as 6 months. Moreover serial MCV studies carried out throughout the first year of life in an affected girl showed no physiological increase in conduction velocity. For purposes of genetic counseling, our experience suggests that, starting from 6 months of age, a clinically and electrophysiologically normal subject has a zero risk of having inherited the HMSN type I gene. However given the limited numbers in this series, infants at risk with normal clinical evaluation and MCVs should be followed up yearly up to 5 years of age.     

Hereditary motor and sensory neuropathy type 1 (HMSN1) associated with cranial neuropathy: an autopsy case report

A family with hereditary motor and sensory neuropathy type 1 (HMSN1) is reported. Three patients suffered only pupillary abnormality, two patients showed Adie's syndrome and peripheral neuropathy, and one had cranial neuropathy. Adie's syndrome and severe peripheral neuropathy. Autopsy of the latter revealed reduction of myelinated nerve fibers in the trigeminal, facial and hypoglossal nerves. There was extensive degeneration of the posterior column of the spinal cord. At the anterior horns, loss of motor neurons was observed, particularly at the lumbar level. The anterior and posterior roots showed loss of myelinated fibers. HMSN1 is only rarely associated with cranial neuropathy, and this is probably the first autopsy-proved case.     

Dominantly inherited peroneal muscular atrophy (hereditary motor and sensory neuropathy type I) in infancy and childhood

A detailed clinical and electrodiagnostic study has been undertaken of demyelinating polyneuropathy in 14 children (9 male, 5 female) from 11 sibships and their parents. The onset of symptoms was before the age of 2 years in 12 of the 14 children, and the condition in all cases was nonprogressive or very slowly progressive. In each case one of the parents had a slow motor nerve conduction velocity. Five of the 11 affected parents were completely asymptomatic. Electrodiagnostic studies in both parents of all children with demyelinating peripheral neuropathy are thus important to identify the dominantly inherited form of the disease.     

Spanish toxic oil syndrome neuropathy in three patients with hereditary motor and sensory neuropathy type I

We describe three patients with hereditary motor and sensory neuropathy type I coming from a family who suffered from Spanish toxic oil syndrome with neuromuscular manifestations. Their clinical course neither differed from other kin only affected with the inherited neuropathy nor from other patients with Spanish toxic oil syndrome studied by us. These findings suggest that patients with hereditary motor and sensory neuropathy do not exhibit a special susceptibility to vasculitic neuropathy associated with Spanish toxic oil syndrome.     

Focal posterior interosseous neuropathy in the presence of hereditary motor and sensory neuropathy,type I

A 30-year-old male with hereditary motor and sensory neuropathy, type I (HMSN I), presented with asymmetric weakness of finger extension and radial deviation with left wrist extension, previously felt to be a manifestation of the peripheral neuropathy. Nerve conduction studies confirmed HMSN I; however, needle EMG revealed marked, ongoing axonal loss in muscles innervated by the left posterior interosseous nerve (PIN) only. At surgery there was focal fusiform swelling in the PIN at exit from the supinator muscle, compatible with localized hypertrophic neuropathy, which has not been reported before in HMSN I. A concomitant focal mononeuropathy should be considered in cases of hereditary neuropathy with marked asymmetry of weakness. © 1996 John Wiley & Sons, Inc.     

Facial nerve dysfunction in hereditary motor and sensory neuropathy type I and III.

Facial nerve function was studied in 19 patients with hereditary motor and sensory neuropathy type I (HMSN I) and 2 patients with hereditary motor and sensory neuropathy type III (HMSN III, Déjérine-Sottas), and compared to that in 24 patients with Guillain-Barré syndrome (GBS). The facial nerve was stimulated electrically at the stylomastoid fossa, and magnetically in its proximal intracanalicular segment. Additionally, the face-associated motor cortex was stimulated magnetically. The facial nerve motor neurography was abnormal in 17 of 19 HMSN I patients and in both HMSN III patients, revealing moderate to marked conduction slowing in both the extracranial and intracranial nerve segments, along with variable reductions of compound muscle action potential (CMAP) amplitudes. The facial nerve conduction slowing paralleled that of limb nerves, but was not associated with clinical dysfunction of facial muscles, because none of the HMSN I patients had facial palsy. Conduction slowing was most severe in the HMSN III patients, but only slight facial weakness was present. In GBS, conduction slowing was less marked, but facial weakness exceeded that in HMSN patients in all cases. We conclude that involvement of the facial nerve is common in HMSN I and HMSN III. It affects the intra- and extracranial part of the facial nerve and is mostly subclinical.     

Decreased axon caliber and neurofilaments in hereditary motor and sensory neuropathy, type I

The axons of large- and intermediate-diameter myelinated fibers of sural nerves of patients with hereditary motor and sensory neuropathy, type I (HMSN-I), were previously found to be attenuated relative to their myelin spiral length. We inferred that axonal atrophy might account for secondary segmental demyelination and remyelination. To assess whether the observed axonal atrophy could be explained by a decrease in neurofilaments, we have evaluated the number of neurofilaments, microtubules, and other axon organelles in sural nerves of patients with HMSN-I. Whereas the density per square micrometer of neurofilaments or microtubules in diseased nerves was not significantly different from that in control specimens, the number of neurofilaments per axon as related to myelin spiral length was significantly less for intermediate and large myelinated fibers in HMSN-I nerves. The regression lines for the number of microtubules per axon on myelin spiral lengths were also less steep in HMSN-I, but the difference did not reach statistical significance. These results indicate that the number of neurofilaments is proportional to axon diameter but significantly below that expected considering myelin spiral length. Decreased neurofilament synthesis, assembly, or transport may underlie the axonal atrophy in HMSN-I.