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Arthrogryposis multiplex congenital, the occurrence of multiple joint contractures at birth, can in some cases be accompanied by insufficient myelination of peripheral nerves, muscular hypotonia, reduced tendon reflexes, and respiratory insufficiency. Recently mutations in the CASPR/CNTN1 complex have been associated with similar severe phenotypes and CNTNAP1 gene mutations, causing loss of the CASPR protein, were shown to cause severe, prenatal onset arthrogryposis multiplex congenita in four unrelated families. Here we report a consanguineous Arab family from Qatar with three children having an early lethal form of arthrogryposis multiplex congenita and a novel frameshift mutation in CNTNAP1. We further expand the existing CNTNAP1-associated phenotype to include profound cerebral and cerebellar atrophy.

Friedreich ataxia (FRDA) is the most common inherited ataxia caused primarily by an intronic GAA.TTC triplet repeat expansion in the frataxin ( FXN ) gene. FXN RNA and protein levels are reduced in patients leading to progressive gait and limb ataxia, sensory loss, reduced tendon reflexes, dysarthria, absent lower limb reflexes, and loss of position and vibration sense. Neurological manifestations ensue from primary loss of dorsal root ganglia neurons and their associated axons ascending centrally in the spinal cord and peripherally in large myelinated nerves. Small noncoding RNAs such as microRNAs have been shown to be dysregulated in neurodegenerative diseases such as Alzheimer's and Huntington's disease. Here we report that hsa-miR-886-3p (miR-886-3p) was increased in patient cells as well as peripheral patient blood samples. Selective reduction in miR-886-3p by an anti-miR led to elevation of FXN message and protein levels without associated changes in histone marks at the FXN locus. Nevertheless, derepression of frataxin by a histone deacetylase inhibitor leads to a decrease in miR-886-3p. These results outline involvement of a small RNA, miR-886-3p in FRDA and a novel therapeutic approach to this disease using an anti-miR-886-3p.

Objectives.Although hereditary neuropathy with liability to pressure palsies (HNPP) presents with a distinct phenotype on history, clinical exam, and nerve conduction studies, it may be masked if diagnostic work-up suggests other causes.Case Report.In a 37-year-old male with pseudoradicular lumbar pain, neurological exam revealed sore neck muscles, peripheral facial nerve palsy, right anacusis and left hypoacusis, hemihypesthesia of the right face, mild distal quadriparesis, diffuse wasting, and generally reduced tendon reflexes. He had a history of skull fracture due to a gunshot behind the right ear and tuberculosis for which he had received adequate treatment for 3 years; MRI revealed a disc prolapse at C6/7 and Th11/12. Nerve conduction studies were indicative of demyelinating polyneuropathy with conduction blocks. Despite elevated antinuclear antibodies and elevated CSF-protein, HNPP was diagnosed genetically after having excluded vasculitis, CIDP, radiculopathy, and the side effects of antituberculous treatment.Conclusions.HNPP may manifest with mild, painless, distal quadriparesis. The diagnosis of HNPP may be blurred by a history of tuberculosis, tuberculostatic treatment, hepatitis, and the presence of elevated CSF-protein.

Hereditary neuropathy with liability to pressure palsy (HNPP; tomaculous neuropathy) is a rare autosomal dominant disorder caused by a loss of function of the peripheral myelin protein 22 gene ( PMP22 ; OMIM #601097) for which no curative treatment exists. Symptoms consist of recurrent painless episodes of focal sensory loss and muscle weakness, which are often provoked by nerve compression and resolve spontaneously within days to months.1 In this report, we describe the case of a female patient with HNPP who initially presented with symptoms of a painful neuropathy which were successfully treated with intravenous immunoglobulin G (IVIg), and the results of a double-blind, placebo-controlled n-of-one trial to assess the effectiveness of IVIg in this patient. In 2002, a 35-year-old female patient presented with a 15-month history of neuropathic pain in the right leg, and recurring episodes of weakness and sensory loss in the legs which resolved spontaneously after several weeks. Her medical and family history was unremarkable. Physical examination showed mild proximal weakness of the left leg (Medical Research Council (MRC) grade 4), severe weakness of the left foot extensors (MRC 0–2), hypoalgesia of the left hand and lower leg, and reduced tendon reflexes with absent Achilles reflexes. All additional investigations were normal, except electromyographic (EMG) studies which showed bilateral demyelinating conduction blocks at ulnar nerve compression sites, prolonged distal motor latencies of the ulnar, tibial, peroneal and median nerves, and absent F-waves in peroneal and right tibial nerves, …

not utilizable. Biopsy of the right gastrocnemius muscle revealed a chronic neurogenic pattern. Since the age of 22 years she noted impaired hearing on the right side. At the age of 26 years, hypothyroidism was diagnosed and levothyroxin prescribed. At the age of 27 years she started to take phentermine to reduce her overweight. Eight weeks later she additionally received nandrolone to compensate for progressive wasting. Three weeks later she stopped phentermine and nandrolone at 100 mg/ week after she had developed blurred vision of the right eye. Ophthalmologic investigation revealed right-sided reduced vision and a papilledema. Clinical neurologic examination revealed distal weakness in all four limbs, with lower limb predominance, and reduced respectively absent deep tendon reflexes. Blood work and CSF investigations were non-informative. Nerve conduction velocities were 18– 22 m/s. Visually-evoked-potentials initially revealed an absent response upon stimulation of the right eye and later on prolongation of the P100 latencies bilaterally. Cerebral MRI was normal. Under corticosteroids, papilledema continuously resolved over weeks. Molecular genetic analysis revealed a common tandem duplication in the PMP22 gene at 17p11.2. HMSN1A was also diagnosed in her father, who had developed sensorimotor deficits and foot deformity without other features as in his daughter since the age of Dear Sir, The autosomal-dominantly inherited 1.5-Mb tandem duplication in the PMP22 gene at 17p11.2 usually manifests as hereditary sensorimotor polyneuropathy with foot deformity (HMSNIA) [1, 2] . In single cases, however, it has been found in association with additional features, such as sensorineural hearing loss, moderate developmental delay, gait disturbance, autism-related disorder, mild dysmorphic features, or growth factor deficiency [3] . The coexistence of sensorimotor polyneuropathy with tremor, ataxia, sensorineural hearing loss, hypothyroidism, short stature, and papilledema has not been reported. The patient is a 27-year-old HIV-negative woman, height 163 cm, weight 73 kg, who had peculiarly walked tiptoe since childhood and had pes cavus. Since the age of 17 years she additionally developed slowly progressive gait disturbance, easy fatigability, and numbness of the distal upper and lower limbs. She had to walk with all her concentration not to stumble. Motor deficits in the lower limbs resulted in inability to climb stairs, difficulties when walking or running, and to get up from the floor without assistance. Diagnostic workup at the age of 20 years revealed distal weakness of all four extremities with rightsided and lower limb predominance, reduced tendon reflexes, muscular hypotonia, and endpoint ataxia. Blood work was normal. Biopsy of the right sural nerve was Received: October 13, 2006 Accepted: October 14, 2006 Published online: December 18, 2006