Subject(s)
Friedreich Ataxia/genetics , Iron-Binding Proteins/genetics , Point Mutation , DNA Mutational Analysis , Diagnosis, Differential , Female , Friedreich Ataxia/diagnosis , Heterozygote , Humans , Introns , Male , RNA Splice Sites , Siblings , Trinucleotide Repeat Expansion , Young Adult , FrataxinABSTRACT
Thalidomide was recently reintroduced to treat several immune-mediated pathologies. Peripheral neuropathy is a significant side effect limiting its clinical use. Our aims include: (1) describing and identifying the incidence of clinical or electrophysiologic peripheral neuropathy in children, (2) determining whether peripheral neuropathy correlates with cumulative dose of thalidomide and with age, and (3) defining its reversibility rate. We studied 13 children manifesting immune-mediated pathologies treated with thalidomide at doses ranging from 25-100 mg/day. Clinical and neurophysiologic evaluation was performed before and after starting treatment. Seven children (53.8%) showed neurophysiologic signs of sensory peripheral axonal polyneuropathy. Five presented associated clinical symptoms, while the other two only presented subclinical, neurophysiologic signs of peripheral neuropathy. We found a significant correlation between the incidence of peripheral neuropathy and thalidomide cumulative dose (P = 0.02). We observed a lower incidence of peripheral neuropathy at a cumulative dose <20 gm, and a correlation with age (P < 0.01). The clinical and electrophysiologic recovery rate was 40%, and clinical improvement alone was observed in another 40%. Thalidomide induces dose-dependent and age-dependent peripheral neuropathy at a significant frequency in childhood (53.8%). In our experience a cumulative dosage at >20 gm and long-term administration for >10 months seem to increase the risk of peripheral neuropathy. We propose clinical and neurophysiologic follow-up every 3 months to identify and monitor possible side effects.
Subject(s)
Immunosuppressive Agents/therapeutic use , Peripheral Nervous System Diseases/drug therapy , Peripheral Nervous System Diseases/physiopathology , Thalidomide/therapeutic use , Action Potentials/drug effects , Action Potentials/physiology , Action Potentials/radiation effects , Adolescent , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Immunosuppressive Agents/metabolism , Immunosuppressive Agents/pharmacology , Infant , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiopathology , Muscle, Skeletal/radiation effects , Neural Conduction/drug effects , Neural Conduction/physiology , Neural Conduction/radiation effects , Peripheral Nervous System Diseases/pathology , Thalidomide/metabolism , Thalidomide/pharmacologyABSTRACT
OBJECTIVE: To define the clinical and laboratory findings in a novel autosomal recessive white matter disorder called hypomyelination and congenital cataract, recently found to be caused by a deficiency of a membrane protein, hyccin, encoded by the DRCTNNB1A gene located on chromosome 7p21.3-p15.3. METHODS: We performed neurological examination, neurophysiological, neuroimaging, and neuropathological studies on sural nerve biopsy in 10 hypomyelination and congenital cataract patients from 5 unrelated families. RESULTS: The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation. Neurophysiological studies showed a slightly to markedly slowed motor nerve conduction velocity in 9 of 10 patients, and multimodal evoked potentials indicated increased central conduction times. Neuroimaging studies demonstrated a diffuse supratentorial hypomyelination, with in some patients, additional areas of more prominent signal change in the frontal region. Sural nerve biopsy showed a slight-to-severe reduction in myelinated fiber density, with several axons surrounded by a thin myelin sheath or devoid of myelin. INTERPRETATION: Hypomyelination and congenital cataract is a novel autosomal recessive white matter disorder characterized by the unique association of congenital cataract and hypomyelination of the central and peripheral nervous system.
Subject(s)
Cataract/congenital , Cataract/physiopathology , Demyelinating Diseases/physiopathology , Hereditary Central Nervous System Demyelinating Diseases/physiopathology , Magnetic Resonance Imaging , Peripheral Nervous System Diseases/physiopathology , Biopsy , Cataract/complications , Cataract/genetics , Cerebellar Ataxia/etiology , Demyelinating Diseases/complications , Demyelinating Diseases/genetics , Female , Genes, Recessive , Hereditary Central Nervous System Demyelinating Diseases/complications , Hereditary Central Nervous System Demyelinating Diseases/diagnosis , Hereditary Central Nervous System Demyelinating Diseases/genetics , Humans , Intellectual Disability/etiology , Intracellular Signaling Peptides and Proteins/deficiency , Male , Membrane Proteins/deficiency , Muscle Spasticity/etiology , Nervous System/pathology , Nervous System/physiopathology , Neural Conduction , Peripheral Nervous System Diseases/complications , Peripheral Nervous System Diseases/genetics , Phenotype , Retrospective Studies , Single-Blind Method , Sural Nerve/pathologySubject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Neural Conduction/drug effects , Peripheral Nervous System Diseases/chemically induced , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Quadriplegia/chemically induced , Vincristine/adverse effects , Antineoplastic Agents, Phytogenic/administration & dosage , Child, Preschool , Drug Administration Schedule , Electrophysiology , Female , Humans , Peripheral Nervous System Diseases/physiopathology , Quadriplegia/physiopathology , Vincristine/administration & dosageABSTRACT
We report a 16-month-old boy with psychomotor regression, muscle hypotonia, peripheral neuropathy, and lactic acidosis. Brain magnetic resonance imaging showed a bilateral abnormal signal in the substantia nigra and in the subthalamic nucleus, suggestive of Leigh disease. Histochemical analysis of skeletal muscle showed decreased cytochrome-c oxidase activity. Biochemical analysis of respiratory chain enzymes in muscle homogenate and in cultured fibroblasts showed isolated cytochrome-c oxidase deficiency. Western blot analysis in fibroblasts showed the absence of Surf1 protein. Genetic analysis of the SURF1 gene revealed that the patient was compound heterozygous for a previously reported mutation at the splice-junction site of intron 3 (240 + 1G > T), and for a novel 4-bp deletion in exon 6 (531_534delAAAT). Our data further enlarge the spectrum of mutations in SURF1 gene in patients with Leigh disease and cytochrome-c oxidase deficiency, contributing to better characterization of the clinical and neuroradiologic features of this group of patients for genotype-phenotype correlations.
