Manuel Roig

Bilateral striatal necrosis associated with a novel mutation in the mitochondrial ND6 gene

We report the molecular findings in two independent patients presenting with progressive generalized dystonia and bilateral striatal necrosis in whom we have identified a mutation (T14487C) in the mitochondrial ND6 gene. The mutation is heteroplasmic in all samples analyzed, and it fulfills all accepted criteria of pathogenicity. Transmitochondrial cell lines harboring 100% mutant mitochondrial DNA showed a marked decrease in the activity of complex I of the respiratory chain supporting the pathogenic role of T14487C.

Genetic analysis of 27 Spanish patients with hemiplegic migraine, basilar-type migraine and childhood periodic syndromes

Familial hemiplegic migraine (FHM) is a rare type of migraine with aura. Mutations in three genes have been described in FHM patients: CACNA1A (FHM1), ATP1A2 (FHM2) and SCN1A (FHM3). We screened 27 Spanish patients with hemiplegic migraine (HM), basilar-type migraine or childhood periodic syndromes (CPS) for mutations in these three genes. Two novel CACNA1A variants, p.Val581Met and p.Tyr1245Cys, and a previously annotated change, p.Cys1534Ser, were identified in individuals with HM, although they have not yet been proven to be pathogenic. Interestingly, p.Tyr1245Cys was detected in a patient displaying a changing, age-specific phenotype that began as benign paroxysmal torticollis of infancy, evolving into benign paroxysmal vertigo of childhood and later becoming HM. This is the first instance of a specific non-synonymous base change being described in a subject affected with CPS. The fact that the molecular screen identified non-synonymous changes in< 15± of our HM patients further stresses the genetic heterogeneity underlying the presumably monogenic forms of migraine.

The clinical spectrum of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

Four patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency are presented. Clinical onset in the form of acute encephalopathy occurred between the ages of 9 months and 3 years. The clinical course included recurrent metabolic crises in 4 patients, cardiac involvement and retinopathy in 3, and myopathy in 2. None had signs of peripheral neuropathy. Three patients died and one is currently well. Hypoketotic hypoglycemia with C6-C14 3-hydroxy-dicarboxylic aciduria during metabolic crises associated with decreased plasma carnitine levels was the main biochemical finding. Enzymologic studies disclosed long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency in all patients. Homozygosity for a G to C mutation at position 1528 in the encoding region of the enzyme was found in 2 patients. Histologic and electron microscopic studies of liver biopsy specimens revealed steatosis in 3 patients and mitochondrial abnormalities in 2. Skeletal muscle biopsies disclosed nonspecific degenerative changes in 2 patients and were normal in the remaining 2. Ultrastructural abnormalities in mitochondria were found in 3 patients. A review of the literature combined with the data from our series (total 22 patients) disclosed acute clinical onset in 77% of cases and subacute in 23%. In the combined series, the average age at onset was 11 months, family history was positive in 32% of patients and overall mortality was 50%. We describe the clinical spectrum of this disease and emphasize that, among patients with suspected beta-oxidation defects the finding of pigmentary retinopathy should lead to the suspicion of long-chain 3-hydroxyacyl-coenzyme A-dehydrogenase deficiency.

Brainstem dysgenesis: report of five patients with congenital hypotonia, multiple cranial nerve involvement, and ocular motor apraxia

This paper reports three females and two males with a distinctive congenital syndrome characterized by severe congenital hypotonia, facial diplegia, jaw ankylosis, velo‐pharyngeal incoordination, pyramidal tract signs, and ocular motor apraxia. Patients were followed up at ages ranging from 20 months to 16 years. All cases of this syndrome are sporadic, without dysmorphological features, chromosomal, or MRI brain abnormalities. Electrophysiological studies indicate the brainstem as the site of the neurological dysfunction. Postmortem CNS study of one of the patients demonstrated neuronal depletion of the IV, VII, VIII, and IX cranial nerve nuclei and intact morphology of the cerebral hemispheres. A vascular accident, early in foetal life, is the most likely cause of the clinical picture. The extent of brainstem involvement and its related clinical findings distinguishes these patients from those with Moebius, Pierre Robin, or Cogan syndromes. Outcome is better than what could be anticipated during the first few months of life given the severity of symptoms. Intelligence or developmental quotients are within the normal range for their age. Facial hypomimia, feeding, and speech articulatory performance difficulties are the main disabilities observed in these patients at follow‐up.

Association study of the serotoninergic system in migraine in the Spanish population.

In order to evaluate the contribution of 19 serotonin‐related genes to the susceptibility to migraine in a Spanish population we performed a case–control association study of 122 single nucleotide polymorphisms (SNPs), selected according to genetic coverage parameters, in 528 migraine patients —308 with migraine without aura (MO) and 220 with migraine with aura (MA)— and 528 sex‐matched migraine‐free controls. The single‐marker analysis identified nominal associations with the migraine phenotype or with the MO or MA subtypes. The multiple‐marker analysis revealed risk haplotypes in three genes that remained significantly associated with migraine after correction by permutations. Two‐marker risk haplotypes were identified in the HTR2B (rs16827801T‐rs10194776G) and MAOA (rs3027400G‐rs2072743C) genes conferring susceptibility to MO, and a four‐marker haplotype in DDC was specific of MA (rs2329340A‐rs11974297C‐rs2044859T‐rs11761683G). The present study supports the involvement of HTR2B and MAOA genes in the genetic predisposition to MO, while DDC might confer susceptibility to MA. These results suggest a differential involvement of serotonin‐related genes in the genetic background of MO and MA.

Acute neurologic dysfunction associated with destructive lesions of the basal ganglia: A benign form of infantile bilateral striatal necrosis

In 1982 Gouti6res and Aicardi ~ described three patients with a syndrome characterized by (1) an abrupt clinical onset after an infectious illness, (2) impaired consciousness, axial hypotonia, motor rigidity, and abnormal movements and postures, (3) sustained improvement of neurologic status, and (4) bilateral low-density lesions of the basal ganglia on the computed tomographie scan. Three similar patients also have been repor ted) 4 It is likely that some other patients described before the advent of modern neuroimaging techniques had this same syndrome) Huntington chorea, Wilson disease, Hallervorden-Spatz syndrome, mitochondrial eneephalomyopathies including Leigh syndrome, familial striatal necrosis, head trauma, hypoxia-ischemia, and various intoxications can occur in childhood with acute or subaeute neurologie dysfunction associated with bilateral low-density lesions in the basal ganglia. The outcome of all of them, however, is poorer than that of acute neurologic dysfunction associated with destructive lesions of the basal ganglia, as described by Gouti6res and Aicardi. 1 We describe two patients with A D B G who had a complete clinical recovery. The CT scan findings in the acute phase of the disease were identical in both patients and supported the diagnosis. Bilateral, symmetric, necrotic lesions of the basal ganglia were found in the magnetic resonance imaging studies from the early stages of the disease and persisted in our second patient up to 5 years later.

Bilateral striatal lesions in childhood

From 1983 to 1991, 13 patients were identified with a clinical radiologic association characterized by acute or persistent neurologic dysfunction and bilateral lesions in the basal ganglia region demonstrated by ultrasound, computed tomography, or magnetic resonance imaging. Initial clinical manifestations of this group of patients were characterized by extrapyramidal signs (i.e., dystonia 9, hypotonia 2, athetosis 1, rigidity 1), altered state of consciousness in 5, and seizures in 3. The outcomes of most of these patients were poor: 10 had motor sequelae, 9 cognitive impairment, and 4 died. The outcomes of 2 patients, however, were much better than what was expected from the initial presentation. Based on current and previous reports, the diagnostic approach and classification of patients with neurologic dysfunction and bilateral striatal lesions are presented.

Familial hemiplegic migraine: linkage to chromosome 14q32 in a Spanish kindred

We sought to map the disease-causing gene in a large Spanish kindred with familial hemiplegic migraine (FHM). Patients were classified according to the ICHD-II criteria. After ruling out linkage to known migraine genetic loci, a single nucleotide polymorphism-based, 0.62-cM density genome-wide scan was performed. Among 13 affected subjects, FHM was the prevailing migraine phenotype in six, migraine with aura in four and migraine without aura in three. Linkage analysis revealed a disease locus in a 4.15-Mb region on 14q32 with a maximum two-point logarithm of odds (LOD) score of 3.1 and a multipoint parametric LOD score of 3.8. This genomic region does not overlap with the reported migraine loci on 14q21–22. Sequence analysis of three candidate genes in the region, SLC24A4, ATXN3 and ITPK1, failed to show disease-causing mutations in our patients. Genetic heterogeneity in FHM may be greater than previously suspected.

Selective muscle fiber loss and molecular compensation in mitochondrial myopathy due to TK2 deficiency

A 12-year-old patient with mitochondrial DNA (mtDNA) depletion syndrome due to TK2 gene mutations has been evaluated serially over the last 10 years. We observed progressive muscle atrophy with selective loss of type 2 muscle fibers and, despite severe depletion of mtDNA, normal activities of respiratory chain (RC) complexes and levels of COX II mitochondrial protein in the remaining muscle fibers. These results indicate that compensatory mechanisms account for the slow progression of the disease. Identification of factors that ameliorate mtDNA depletion may reveal new therapeutic targets for these devastating disorders.

Progressive vacuolating glycine leukoencephalopathy with pulmonary hypertension.

To report two unrelated patients with a new phenotype of nonketotic hyperglycinemia associated with idiopathic pulmonary hypertension. Clinical findings included rapidly progressive neurological deterioration with onset in the first year of life characterized by developmental regression without seizures or electroencephalogram abnormalities during follow‐up. Both patients died before the age of 18 months. Glycine cleavage system deficiency was confirmed by enzymatic studies in frozen liver. Molecular analysis in the related genes showed no pathogenic mutation. Radiological and pathological findings were consistent with progressive vacuolating encephalopathy. Our patients with biochemical and enzymatic parameters consistent with atypical nonketotic hyperglycinemia. The clinical and radiological evolution, as progressive vacuolating leukoencephalopathy and the association with pulmonary hypertension constitute a previously unrecognized variant. Ann Neurol 2006;60:148–152