Report of a Transligamentous Ulnar Nerve Sensory Branch.

Background: Several anatomical variations of the median nerve recurrent motor branch have been described. No previous reports have described the anatomical variation of the ulnar nerve with respect to transverse carpal ligament. In this article, we present a patient with symptomatic compression of the ulnar nerve found to occur outside the Guyon canal due to a transligamentous course through the distal transverse carpal ligament. Methods: A 59-year-old, right-hand-dominant male patient presented with right hand pain, subjective weakness, and numbness in both the ulnar and the median nerve distributions. Electromyography revealed moderate demyelinating sensorimotor median neuropathy at the wrist and distal ulnar sensory neuropathy. At the time of planned carpal tunnel and Guyon canal release, a transligamentous ulnar nerve sensory common branch to the fourth webspace was encountered and safely released. Results: There were no surgical complications. The patient's symptoms of numbness in the median and ulnar nerve distribution clinically improved at his first postoperative visit. Conclusions: We have identified a case of transligamentous ulnar nerve sensory branch encountered during carpal tunnel release. To our knowledge, this has not been previously reported. While the incidence of this variant is unknown, hand surgeons should be aware of this anatomical variant as its location puts it at risk of iatrogenic injury during open and endoscopic carpal tunnel release.

A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts.

N-Glycanase 1, encoded by NGLY1, catalyzes the deglycosylation of misfolded N-linked glycoproteins retrotranslocated into the cytosol. We identified nine cases with mutations in NGLY1. The patients show developmental delay, seizures, peripheral neuropathy, abnormal liver function and alacrima (absence of tears). The mutations in NGLY1 resulted in the absence of N-glycanase 1 protein in patient-derived fibroblasts. Applying a recently established cellular deglycosylation-dependent Venus fluorescence assay, we found that patient fibroblasts had dramatically reduced fluorescence, indicating a pronounced reduction in N-glycanase enzymatic activity. Using this assay, we could find no evidence of other related activities. Our findings reveal that NGLY1 mutations destroy both N-glycanase 1 protein and enzymatic activity.

Congenital cataracts, facial dysmorphism, and neuropathy syndrome.

Congenital cataracts, facial dysmorphism, and neuropathy syndrome is a delineated genetic disease exclusively manifested in the Roma population. The pattern of inheritance is autosomal recessive, and a causative mutation is evident in the CTDP1 gene. Affected patients display congenital cataracts, microcornea, peripheral neuropathy, mild facial dysmorphism, hypogonadism, and psychomotor delay. We present the second case of this syndrome in a Greek Roma family, diagnosed in early infancy, along with the prenatal diagnosis in a subsequent pregnancy.

A case of congenital axonal neuropathy associated with West syndrome.

We report the case of an 11-month-old girl with congenital axonal neuropathy and West syndrome. She had generalized hypotonia and an abnormal posture since birth, and apparently, her development was stalled. Deep tendon reflexes were absent, and at 5 months of age, she developed West syndrome followed by refractory seizures. Magnetic resonance imaging of the brain revealed mild cerebral and cerebellar atrophy, high-signal-intensity areas in the white matter, and hypoplasia of the corpus callosum. No action potentials were detected in both lower and upper extremities in motor and sensory conduction velocity analysis performed at 11 months of age. Sural nerve biopsy was performed, and analysis of the biopsied specimen revealed axonal degeneration. Originally designed resequencing analysis using microarray was carried out for the 27 genes associated with Charcot-Marie-Tooth disease, but no disease-causing mutations were identified. So far, there have been no reports on simultaneous development of congenital axonal neuropathy and West syndrome.

Krox20 inactivation in the PNS leads to CNS/PNS boundary transgression by central glia.

CNS/PNS interfaces constitute cell boundaries, since they delimit territories with different neuronal and glial contents. Despite their potential interest in regenerative medicine, the mechanisms restricting oligodendrocytes and astrocytes to the CNS, and Schwann cells to the PNS in mammals are not known. To investigate the involvement of peripheral glia and myelin in the maintenance of the CNS/PNS boundary, we have first made use of different mouse mutants. We show that inactivation of Krox20/Egr2, a master regulatory gene for myelination in Schwann cells, results in transgression of the CNS/PNS boundary by astrocytes and oligodendrocytes and in myelination of nerve root axons by oligodendrocytes. In contrast, such migration does not occur with the Trembler(J) mutation, which prevents PNS myelination without affecting Krox20 expression. Altogether these data suggest that maintenance of the CNS/PNS boundary requires a new Krox20 function separable from myelination control. Finally, we have analyzed a human patient affected by a congenital amyelinating neuropathy, associated with the absence of the KROX20 protein in Schwann cells. In this case, the nerve roots were also invaded by oligodendrocytes and astrocytes. This indicates that transgression of the CNS/PNS boundary by central glia can occur in pathological situations in humans and suggests that the underlying mechanisms are common with the mouse.

Hereditary neuropathy with liability to pressure palsy (HNPP) in childhood: a case study emphasizing the relevance of detailed electrophysiological examination for suspected HNPP in the first decade.

Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disorder characterized by recurrent mono-neuropathies secondary to minor trauma or compression. Whilst typical episodes of palsy generally become apparent during the second and the third decades, HNPP is rarely diagnosed in the first decade. We present the case of a 6-year-old patient to draw attention to the possibility of HNPP attacks in the first decade and the importance of detailed electrophysiological examination.

Congenital axonal neuropathy and encephalopathy.

Congenital axonal neuropathy associated with encephalopathy appears to be very rare. Only a few cases have been reported in the literature. In the last 25 years, we have seen seven patients affected by congenital axonal neuropathy with encephalopathy. Biopsies of their sural nerves revealed axonal atrophy and loss of large-diameter nerve fibers. All of these patients presented at birth or soon thereafter with hypotonia associated with distal weakness and diffuse areflexia. Central nervous system manifestations included microcephaly, seizures, and developmental delay. Outcomes were poor. Four children died before age 3 years from respiratory insufficiency or aspiration pneumonia. The three surviving patients manifested severe developmental delay. In our most recent patient, Western-blot analysis of snap-frozen specimens of the temporal and cerebellar cortex demonstrated an absence or marked decrease of microtubule-associated protein types 1A and 2, compared with age-matched control subjects. Calloso-splenial hypogenesis and neurofilament swellings were also documented in the deep white matter and adjacent cortex. The absence or hypo-expression of central nervous system microtubule-associated proteins has never been reported in congenital neuropathies, and may represent a new clinicopathologic entity.

Cardiofaciocutaneous syndrome (CFC) with congenital peripheral neuropathy and nonorganic malnutrition: an autopsy study.

Many phenotypic manifestations have been reported in cardiofaciocutaneous (CFC) syndrome, but none, to date, are pathognomonic or obligatory. Previous histopathological studies reported findings in skin and hair; no autopsy studies have been published. We report the clinical and autopsy findings of a 7-year-old boy with severe CFC syndrome and malnutrition of psychosocial origin. Manifestations of CFC, reported previously, included macrocephaly and macrosomia at birth; short stature; hypotonia; global developmental delays; dry, sparse thin curly hair; sparse eyebrows and eyelashes; dilated cerebral ventricles; high cranial vault; bitemporal constriction; supraorbital ridge hypoplasia; hypertelorism; ptosis; exophthalmos; depressed nasal bridge; anteverted nostrils; low-set, posteriorly-rotated, large, thick ears; decayed, dysplastic teeth; strabismus; hyperelastic skin; wrinkled palms; keratosis pilaris atrophicans faciei; ulerythema ophryogenes; hyperkeratosis; gastroesophageal reflux; and tracheobronchomalacia. Additional findings, not previously reported, include islet cell hyperplasia, lymphoid depletion, thymic atrophy and congenital hypertrophy of peripheral nerves with onion bulb formations. Although the islet cell hyperplasia, lymphoid depletion, and thymic atrophy are nonspecific findings that may be associated with either CFC or malnutrition, the onion bulb hypertrophy is specific for a demyelinating-remyelinating neuropathy. These findings implicate congenital peripheral neuropathy in the pathogenesis of the developmental delays, feeding difficulties, respiratory difficulties, ptosis and short stature in this case. Additional studies of other cases of CFC are needed.

Hereditary neuropathy with liability to pressure palsies (HNPP) in a toddler presenting with toe-walking, pain and stiffness.

The typical clinical presentation of hereditary neuropathy with liability to pressure palsies is an adult-onset recurrent, painless monoparesis. Electrophysiological abnormalities--decreased nerve conduction velocities and delayed distal latencies--can be detected even in asymptomatic patients. We describe a toddler, who presented with asymmetric toe walking, painful cramps and stiffness in the legs. He had calf hypertrophy, brisk tendon reflexes and bilateral Babinski signs and the electrophysiological examination was normal. The unlikely diagnosis of hereditary neuropathy with liability to pressure palsies was reached 5 years later, when the boy started to complain of episodic numbness and weakness in the upper extremities. His father, paternal aunt and grandmother had similar symptoms, but they had never been investigated. The typical 1.5 Mb deletion on chromosome 17p11.2-12 was found in our patient and his affected relatives.

Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation.

A unique phenotype of Waardenburg-Hirschsprung disease (WS4) accompanied by peripheral neuropathy and central dysmyelination has been recognized recently in association with SOX10 mutations. We report an infant boy with lethal congenital hypomyelinating neuropathy and WS4 who had a heterozygous SOX10 mutation (Q250X). Histopathological studies showed an absence of peripheral nerve myelin despite normal numbers of Schwann cells and profound dysmyelination in the central nervous system. These observations suggest that some SOX10 mutations such as Q250X may allow Schwann cells and oligodendrocytes to proliferate but interfere with further differentiation to form myelin. In contrast with the SOX10 loss-of-function mutations causing only WS4, mutations associated with both peripheral and central dysmyelination may affect pathology through a dominant-negative mechanism.

P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves.

We show that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, myelin protein zero (Mpz). Transgenic mice containing extra copies of Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested myelination and impaired sorting of axons by Schwann cells. Myelination was restored by breeding the transgene into the Mpz-null background, demonstrating that dysmyelination does not result from a structural alteration or Schwann cell-extrinsic effect of the transgenic P(0) glycoprotein. Mpz mRNA overexpression ranged from 30-700%, whereas an increased level of P(0) protein was detected only in nerves of low copy-number animals. Breeding experiments placed the threshold for dysmyelination between 30 and 80% Mpz overexpression. These data reveal new points in nerve development at which Schwann cells are susceptible to increased gene dosage, and suggest a novel basis for hereditary neuropathy.

Congenital muscular dystrophy with central and peripheral nervous system involvement in a Belgian patient.

We report a patient with congenital muscular dystrophy (CMD), developmental brain defects, and peripheral neuropathy. Marked hypotonia and plagiocephaly were noted at birth. Failure to thrive, generalized muscle weakness and wasting, absent deep tendon reflexes, partial seizures, and secondary microcephaly developed. Brain MRI showed a large area of cortical dysplasia, a thin but complete corpus callosum, and diffuse ventriculomegaly. Nerve conduction velocities were slow and creatine kinase levels only mildly elevated. Muscle biopsy showed dystrophic features with normal merosin, sarcoglycan, and dystrophin immunostaining. The Japanese Fukuyama CMD founder mutation was not detected. This is the first report of a patient with merosin-positive CMD, cobblestone lissencephaly, and demyelinating peripheral neuropathy.

Unsuccessful surgical treatment of hip dislocation in congenital sensory neuropathy with anhidrosis. A case report.

A six-year-old girl with congenital sensory neuropathy with anhidrosis (CSNA) presented with bilateral hip dysplasia and subluxation on the right side. Conservative treatment of the hips by closed reduction and a plaster cast was unsuccessful. When aged seven years the patient had an intertrochanteric varus rotation osteotomy on the right side, but subluxation was again evident after five months. A Salter-type pelvic osteotomy was carried out followed by immobilisation, but one year later subluxation was present in the right hip and dislocation in the left. At the age of nine years, the right femoral head resembled a Charcot joint, although walking ability was preserved. In patients with CSNA, surgery may not always be advisable.

Hereditary peripheral neuropathies: clinical forms, genetics, and molecular mechanisms.

Hereditary peripheral neuropathies, among the most common genetic disorders in humans, are a complex, clinically and genetically heterogeneous group of disorders that produce progressive deterioration of the peripheral nerves. This group of disorders includes hereditary neuropathy with liability to pressure palsies, Charcot-Marie-Tooth disease, Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy. Our understanding of these disorders has progressed from the description of the clinical phenotypes and delineation of the electrophysiologic and pathologic features to the identification of disease genes and elucidation of the underlying molecular mechanisms.

Lissencephaly associated with congenital hypomyelinating and axonal neuropathy.

The authors describe an 11-year-old male with severe mental retardation, hypotonia, and arthrogryposis, with both type I lissencephaly and a congenital peripheral neuropathy, probably hypomyelinating with axonal involvement. To the best of the authors' knowledge, this is the first report involving the co-occurrence of these two developmental disorders. A viral, metabolic, or nutritional insult acting throughout the period of migration and myelination or a contiguous gene linkage are possible explanations for this disorder.

Laryngeal paralysis-polyneuropathy complex in young Rottweilers.

Five Rottweiler puppies from 3 unrelated litters developed inspiratory stridor at 11-13 weeks of age. Physical examination disclosed tetraparesis in all dogs, and bilateral lenticular cataracts in 4 dogs. Laryngeal examination under light anesthesia showed laryngeal paralysis in all dogs. Electrodiagnostic testing revealed denervation potentials in the distal appendicular muscles of 4 dogs tested and in the intrinsic laryngeal muscles of 2 dogs tested. Motor nerve conduction velocity was slightly low in 1 dog. Neurogenic muscular atrophy was found in distal appendicular muscles (n = 3) and intrinsic laryngeal muscles (n = 2), and degenerative changes were found in peripheral nerves (n = 3) and recurrent laryngeal nerves (n = 2). No abnormalities were detected in the spinal cord, spinal nerve roots, or ganglia of 3 dogs autopsied. The clinical, electrophysiologic, and histopathologic findings support a diagnosis of polyneuropathy and resemble the finding reported in young Dalmatians. Young dogs with laryngeal paralysis should be evaluated neurologically to rule out a more generalized polyneuropathy. The condition is suspected to be hereditary in nature and the prognosis is poor.

Neuromuscular disorders in the newborn.

The main manifestations of neuromuscular disease in the newborn period are hypotonia and weakness. Infants with severe hypotonia but only marginal weakness usually do not have a disorder of the lower motor unit. These infants may have genetic conditions, metabolic disturbances, congenital heart disease, hypothyroidism, sepsis, or other systemic disorders. Early on, neonates with central nervous system pathology may present with profound hypotonia, decreased reflexes, and moderate to severe but transient weakness. However, they also tend to have seizures, obtundation, cranial nerve signs, or history of perinatal asphyxia.

Sequential study of central and peripheral nervous system involvement in an infant with merosin-deficient congenital muscular dystrophy.

Diffuse white matter changes on brain imaging and peripheral neuropathy are associated features of merosin-deficient congenital muscular dystrophy (CMD). In this report we describe the early manifestation and evolution of brain changes, and the involvement of the peripheral nervous system in a female infant with merosin-deficient CMD diagnosed in the neonatal period who had sequential clinical, neurophysiological and magnetic resonance imaging (MRI) assessment. Both MRI and nerve conduction velocity in the first week of life failed to demonstrate any abnormality. By 6 months of age both nerve conduction and MRI were abnormal. White matter changes became more evident on a further scan at 1 yr of age and this pattern remained unchanged on the following scan performed at 17 months of age. Our findings suggest a failure in the physiological maturation process of myelination of both the central and peripheral nervous system.