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PubMed2004

Hereditary neuropathy with liability to pressure palsy: fulminant development with axonal loss during military training.

Hereditary neuropathy with liability to pressure palsy (HNPP) is characterised by recurrent mononeuropathies following minor trauma. We describe a case of fulminant HNPP beginning on the first day of military physical training. Protracted weakness, muscle atrophy, hand contractures, and multifocal sensory loss developed during a further three weeks of basic training. Nerve conduction changes were typical of HNPP, but without segmental slowing. Electromyographically, there was prominent acute denervation in muscles of the hands and right shoulder. Sural nerve biopsy demonstrated tomaculae and remyelination. Genetic testing revealed PMP-22 gene deletion. This case report demonstrates that HNPP can present with rapidly progressive peripheral nerve dysfunction and electrophysiological evidence of focal axonal loss.

Adult↗
PubMed2003

Insights into the molecular basis of polyglutamine neurodegeneration from studies of a spinocerebellar ataxia type 7 mouse model.

Spinocerebellar ataxia type 7 (SCA7) is one member of a growing list of neurodegenerative disorders that are all caused by CAG repeat expansions that produce disease by encoding elongated polyglutamine tracts in a variety of apparently unrelated proteins. In this review, we provide an overview of our efforts to determine the molecular basis of polyglutamine neurotoxicity in SCA7 by modeling this polyglutamine repeat disorder in mice. We discuss how our SCA7 mouse model develops a phenotype that is reminiscent of the retinal and cerebellar disease pathology seen in human patients. All of these findings are considered in the context of numerous other models of polyglutamine disease pathology in mice and other organisms, together with various other in vitro and biochemical studies. We present the competing hypotheses of polyglutamine disease pathogenesis, and explain how our studies of SCA7 brainstem and retinal degeneration using this mouse model have yielded insights into possible mechanisms and pathways of polyglutamine disease pathology. In addition to illustrating how our SCA7 mouse model has allowed us to develop and advance notions of disease pathogenesis, we propose a model of polyglutamine molecular pathology that attempts to integrate the key observations in the field. We close by describing why our SCA7 mouse model should be useful for the next phase of polyglutamine disease research--the development of therapies, and predict that this stage of experimentation will continue to rely heavily on the mouse.

Ataxin-7↗
PubMed2001

Multiple neuroendocrine disorder in Salla disease.

Salla disease represents the slowly progressive adult form of the sialic acid storage diseases, a group of autosomal-recessive neurodegenerative disorders in which psychomotor development, ataxia, axial hypotonia, and spasticity in the lower limbs occur. No skeletal dysostosis or organomegaly is present, and life expectancy is normal. Short stature can also be observed. Progressive cerebral and cerebellar atrophy associated with dysmyelination and corpus callosum hypoplasia have been shown by magnetic resonance imaging studies. We report the first patient with Salla disease in whom combined growth hormone and gonadotropin deficiencies, hypothalamic pituitary in origin, have been demonstrated by neuroendocrine studies. We believe that the multiple neuroendocrine disorder may be the consequence of the abnormalities of common neuronal pathways regulating growth hormone and gonadotropin synthesis or secretion related to the brain storage of free sialic acid and/or to the neurodegenerative process occurring in Salla disease. Therefore, a complete endocrinologic evaluation of these patients is both warranted and useful.

Adolescent↗
PubMed2003

Andermann syndrome in a Turkish patient.

Agenesis of the corpus callosum with peripheral neuropathy or Andermann syndrome is an autosomal recessive disorder rarely found outside certain regions of the province of Quebec, Canada. We report a 5-year-old Turkish patient with Andermann syndrome born to consanguineous parents. She presented with diffuse hypotonic weakness, predominantly in the distal extremities, and mild mental retardation. Electromyography showed axonal-demyelinating sensorimotor neuropathy. Sural nerve biopsy was compatible with demyelinating neuropathy. Cranial magnetic resonance imaging revealed total agenesis of the corpus callosum, dilatation of the interhemispheric fissure, and enlargement of the cisterna magna. The molecular genetic analysis using microsatellite DNA markers covering the agenesis of the corpus callosum with peripheral neuropathy locus on chromosome 15q13-q15 showed that the patient is homozygous for the whole region. Our findings confirm that Andermann syndrome is a genetically homogeneous disorder.

Agenesis of Corpus Callosum↗
PubMed2003

Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic.

The authors describe a patient with hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) who has two compound heterozygote mutations of the PANK2 gene. IVS4-1 G>T segregates with the lipid and erythrocyte changes in the mother and sister. No other family members have the lipid, erythrocyte, or clinical abnormalities. The father and two brothers are heterozygous for Met327Thr. One other mutation has been found in this PANK2 region associated with the HARP phenotype, suggesting a local genotype effect.

Acanthocytes↗
PubMed2004

Infantile bilateral striatal necrosis maps to chromosome 19q.

BACKGROUND: Infantile bilateral striatal necrosis (IBSN) encompasses several syndromes of bilateral symmetric degeneration of the caudate nucleus, putamen, and globus pallidus. Autosomal recessive IBSN is characterized clinically by developmental arrest beginning at age 7 to 15 months, dysphagia, choreoathetosis, pendular nystagmus and optic atrophy, and severe progressive atrophy of the basal ganglia on MRI. OBJECTIVE: To map the gene causing IBSN. METHODS: A 10-cM genome-wide linkage scan was initially performed on five affected and five unaffected individuals. The extended family was included in the analysis to narrow the candidate region. Logarithm of odds (LOD) score was calculated using the SUPERLINK program. RESULTS: Linkage to the chromosomal region 19q13.32-13.41 was established (Z(max) = 6.27 at theta = 0.02 at locus D19S412). Recombination events and a common disease-bearing haplotype defined a critical region of 1.2 Mb between the loci D19S596 proximally and D19S867 distally. CONCLUSION: IBSN maps to the chromosomal region 19q13.32-13.41. The presence of a common haplotype in all the patients suggests that the disease is caused by a single mutation derived from a single ancestral founder in all the families.

Age of Onset↗
PubMed2004

Multiparametric MRI in a patient with adult-onset leukoencephalopathy with vanishing white matter.

This is a multiparametric MR study of the first reported patient with adult-onset genetically confirmed vanishing white matter (VWM) disease. It shows that, despite the presence of a severe and diffuse damage of the brain WM, brain gray matter, and cervical cord tissue, the cortical adaptive capacities were relatively preserved. Interpatient variability of brain plasticity may contribute to the known phenotypic variation of patients with VWM disease.

Basal Ganglia↗
PubMed2005

Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations.

OBJECTIVE: To investigate three families and one sporadic case with a recessively inherited ataxic syndrome. METHODS: Clinical and genetic studies were performed in six individuals. Southern blotting and real time PCR were used to detect deletions of mtDNA and mutations in the POLG gene were identified using a combination of DHPLC and direct DNA sequencing. RESULTS: The patients have a distinctive, progressive disorder that starts with episodic symptoms such as migraine-like headache or epilepsy. Ataxia, which is a combination of central and peripheral disease, develops later as does ophthalmoplegia. The commonest form of epilepsy was focal and involved the occipital lobes. Myoclonus was common and patients have a high risk of status epilepticus. MRI typically shows signal changes in the central cerebellum, olivary nuclei, occipital cortex, and thalami. COX negative muscle fibers were found in four of six; in one patient these were rare and in another absent. Multiple mtDNA deletions were identified in all patients, although in two these were not apparent on Southern blotting and real time PCR was required to demonstrate the defect. Two families were homozygous for a previously described POLG mutation, G1399A (A467T). One family and the sporadic case had the same two new mutations, a G to C at position 1491 (Q497H) and a G to C at 2243 (W748S). CONCLUSIONS: Mutations in POLG cause a recessively inherited syndrome with episodic features and progressive ataxia. Characteristic changes on MRI are seen and although skeletal muscle may appear morphologically normal, multiple mtDNA deletions can be detected using real-time PCR.

Adolescent↗
PubMed2005

The natural history of Aicardi-Goutières syndrome: follow-up of 11 Italian patients.

Described are the outcomes of 11 Italian patients with Aicardi-Goutières syndrome. Neurologic symptoms progressed in the first year of life and stabilized by the end of the second year in 10 patients. White matter abnormalities remained stable; cerebral atrophy was stable in four patients and progressive in two. Calcifications increased (in number and size) in two of six patients. Serial CSF and serum interferon-alpha measurements (three patients) showed reduced CSF interferon-alpha levels.

Abnormalities, Multiple↗
PubMed2005

The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal-recessive disorder caused by mutations in the PANK2 gene. The authors report clinical and genetic findings of 16 patients with PKAN. The authors identified 12 mutations in the PANK2 gene, five of which were new. Only nine patients could be classified as classic or atypical PKAN, and intermediate phenotypes are described. Two patients presented with motor tics and obsessive-compulsive behavior suggestive of Tourette syndrome.

Adolescent↗
PubMed2005

CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics.

BACKGROUND: CACNA1A encodes CaV2.1, the pore-forming subunit of P/Q-type voltage-gated calcium channel complexes. Mutations in CACNA1A cause a wide range of neurologic disturbances variably associated with cerebellar degeneration. Functional studies to date focus on electrophysiologic defects that do not adequately explain the phenotypic findings. OBJECTIVE: To investigate whether some missense mutations might interfere with protein folding and trafficking, eventually leading to protein aggregation and neuronal injury. METHODS: The authors studied the functional consequences of two pore missense mutations, C287Y and G293R, in two families with EA2, one newly discovered and the other previously reported. Both mutations caused episodic and interictal ataxia. The biophysical properties of mutant and wild type calcium channels were examined by whole-cell patch-clamp recordings in transfected COS-7 cells. The plasma membrane targeting was visualized by confocal fluorescence imaging on CaV2.1 tagged with green fluorescent protein. RESULTS: The mutant channels exhibited a marked reduction in current expression and deficiencies in plasma membrane targeting. CONCLUSIONS: In addition to altered channel function, the deficiency in protein misfolding and trafficking associated with the C287Y and G293R mutants may contribute to the slowly progressive cerebellar ataxia.

Adolescent↗
PubMed2002

Familial infantile bilateral striatal necrosis: clinical features and response to biotin treatment.

BACKGROUND: Infantile bilateral striatal necrosis (IBSN) encompasses several syndromes of bilateral symmetric, spongy degeneration of the caudate nucleus, putamen, and globus pallidus. The familial form of IBSN is rare, and inheritance is either autosomal recessive or maternal. METHOD: The authors describe an Israeli Bedouin kindred in which 15 children born to consanguineous parents were affected with familial IBSN. They evaluated the clinical and radiologic evolution of the disease in 11 patients and the cerebral pathologic findings in one patient. Three of the children were treated with oral biotin 100 mg/day. RESULTS: Inheritance was apparently autosomal recessive. The untreated children had a similar clinical picture including developmental arrest beginning at the age of 7 to 15 months, choreoathetosis, and dysphagia. Pendular nystagmus appeared at a late stage. MRI, performed at various stages of the disease, showed severe basal ganglia atrophy. Postmortem study in one patient showed severe atrophy of the lenticular nuclei with gliosis and loss of neurons. Biotin, 100 mg/day, administered to the proband over a period of 15 months, may have slowed progression. In two other children treatment was initiated earlier and appeared to arrest or improve disease. CONCLUSIONS: Familial infantile bilateral striatal necrosis was inherited as an autosomal recessive trait. Clinical features included developmental arrest, dysphagia, and choreoathetosis. Imaging and pathology showed atrophy and degeneration of the basal ganglia. Oral biotin may have benefited three children.

Basal Ganglia Diseases↗
PubMed2004

Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila.

Beta-amyloid peptides that are cleaved from the amyloid precursor protein (APP) play a critical role in Alzheimer's disease (AD) pathophysiology. Here, we show that in Drosophila, the targeted expression of the key genes of AD, APP, the beta-site APP-cleaving enzyme BACE, and the presenilins led to the generation of beta-amyloid plaques and age-dependent neurodegeneration as well as to semilethality, a shortened life span, and defects in wing vein development. Genetic manipulations or pharmacological treatments with secretase inhibitors influenced the activity of the APP-processing proteases and modulated the severity of the phenotypes. This invertebrate model of amyloid plaque pathology demonstrates Abeta-induced neurodegeneration as a basic biological principle and may allow additional genetic analyses of the underlying molecular pathways.

Age Factors↗