Gaetano S. Grieco

Ataxia with oculomotor apraxia type 2: A clinical, pathologic, and genetic study

Background: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients. Objective: To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families. Methods: The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations. Results: All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation). Conclusions: The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin.

Familial basilar migraine associated with a new mutation in the ATP1A2 gene

Basilar migraine (BM), familial hemiplegic migraine (FHM), and sporadic hemiplegic migraine (SHM) are phenotypically similar subtypes of migraine with aura, differentiated only by motor symptoms, which are absent in BM. Mutations in CACNA1A and ATP1A2 have been found in FHM. The authors detected a novel mutation in the ATP1A2 gene (R548H) in members of a family with BM, suggesting that BM and FHM may be allelic disorders.

Clinical and genetic studies in hereditary spastic paraplegia with thin corpus callosum

Background: A complicated form of recessive hereditary spastic paraplegias (HSPs) with thin corpus callosum (TCC) was first described in Japan, and most of the Japanese families showed linkage to chromosome 15q13–15. A recessive HSP locus (SPG11) has also been mapped to chromosome 15q13–15 in Italian and North American families with and without TCC, and it overlaps the region identified in the Japanese families. Objective: To study clinically and genetically 12 Italian families with HSP and TCC. Methods: The authors investigated 18 affected and 30 healthy individuals from 12 unrelated Italian families with recessive HSP-TCC. Clinical, neurophysiologic, and neuroradiologic studies were undertaken. All patients were negative for SPG7 mutations. Genetic linkage analyses were carried out with polymorphic DNA markers on 15q13–15. Results: Five families were consistent with linkage, thus defining a 19.8-cM region between markers D15S1007 and D15S978, encompassing the SPG11 interval. In one consanguineous family, linkage could be firmly excluded, confirming genetic heterogeneity. Two families appeared not linked to the region, but this could not be firmly proved because of the small family size. The remaining four families were uninformative for linkage purposes. Conclusion: HSP-TCC is common in Italy. The phenotype is fairly homogeneous and is associated with impaired cognition. There are at least two loci for HSP-TCC, one of which is on chromosome 15q13–15.

Novel SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay type

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset familial disease with prominent myelinated fibers in the optic fundus. ARSACS is frequent in the Charlevoix-Saguenay region of Quebec but rare elsewhere. Mutations in SACS, encoding sacsin, a protein of unknown function, are associated with ARSACS. The authors identified three new SACS mutations in two Italian patients whose phenotype closely matches that of Quebec cases, but without retinal striation.

MITOCHONDRIAL DNA HAPLOGROUPS INFLUENCE THE THERAPEUTIC RESPONSE TO RIBOFLAVIN IN MIGRAINEURS

Objectives: In migraine, an interictal reduction of mitochondrial energy metabolism and a preventive effect of high-dose riboflavin were reported. To explore the relation between the two, we tested if the therapeutic response to riboflavin is associated with specific mitochondrial DNA (mtDNA) haplogroups. We focused our attention on haplogroup H, which is known to differ from others in terms of energy metabolism. Methods: Sixty-four migraineurs completed a 4-month open trial with riboflavin (400 mg QD) and were genotyped blindly for mtDNA haplogroups. Results: Forty patients responded to riboflavin treatment and 24 were nonresponders. The mtDNA haplogroup H was found in 29 subjects (20 migraine without aura, 9 migraine with aura). Riboflavin responders were more numerous in the non-H group (67.5%). Conversely, nonresponders were mostly H (66.7%). The difference between the two groups was significant (χ2 = 7.07; p = 0.01). The presence of aura had no influence on riboflavins effectiveness (χ2 = 0.113; p = 0.74) and was not associated with a particular haplogroup (χ2 = 0.55; p = 0.46). Conclusions: In this pharmacogenetic study, riboflavin appears to be more effective in patients with migraine with non-H mitochondrial DNA haplotypes. The underlying mechanisms are unknown, but could be related to the association of haplogroup H with increased activity in complex I, which is a major target for riboflavin. Our results may have ethnic implications, since haplogroup H is chiefly found in the European population.

A Novel ATP1A2 Mutation in a Family with FHM Type II

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura with an autosomal dominant pattern of inheritance. Six FHM families underwent extensive clinical and genetic investigation. The authors identified a novel ATP1A2 mutation (E700K) in three patients from one family. In the patients, attacks were triggered by several factors including minor head trauma. In one subject a 3-day coma developed after a cerebral angiography. Overall, the phenotype of the patients closely resembles that of previously reported cases of FHM type II. The E700K variant might be regarded as the cause of the disease in this family, but this was not tested functionally.

Multicentre Italian family-based association study on tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders.

Objective The aim of the present study was to investigate tyrosine hydroxylase, catechol‐O‐methyl transferase and Wolfram syndrome 1 genes in mood disorders using a family‐based association approach. Methods The sample included 134 nuclear mood disorder families, with subjects affected by bipolar disorder (n= 103) or major depressive disorder (n=58). All subjects were genotyped using polymerase chain reaction techniques. Results No significant transmission disequilibrium was found in the overall sample for any polymorphism. Analysis considering bipolar subjects only, or psychopathology traits as affection status did not influence the observed results. Conclusions The study could not support the involvement of tyrosine hydroxylase, catechol‐O‐methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders.

The wolframin His611Arg polymorphism influences medication overuse headache

Homozygosis for wolframin (WFS1) mutations determines Wolfram syndrome (WS), and common polymorphisms of WFS1 are associated with psychiatric illnesses and dependence behaviour. To test the influence of WFS1 polymorphisms on medication overuse headache (MOH), a chronic headache condition related to symptomatic drugs overuse, we analyzed 82 MOH patients for the WFS1 His611Arg polymorphism, and performed a comparison between clinical features of Arg/Arg (R/R) and non-R/R individuals. Individuals harbouring the R/R genotype showed significantly higher monthly drug consumption (t=-3.504; p=0.00075) and more severe depressive symptoms on the BDI questionnaire (t=-3.048; p=0.003) than non-R/R. WFS1 polymorphism emerged as the only significant predictor of drug consumption, at the multivariate regression analysis (F=12.277; d.f.=1,80; p=0.00075, adjusted R2=0.122). These results implicate WFS1 in the clinical picture of MOH, may be through an influence on need for drugs as in other conditions of abuse behaviour.

Cortical response to somatosensory stimulation in medication overuse headache patients is influenced by angiotensin converting enzyme (ACE) I/D genetic polymorphism

Background Medication overuse headache (MOH) is a disabling health problem. Convincing evidence attributes a pathophysiologic role to central sensitization. By recording somatosensory evoked potentials (SSEPs) in patients with MOH, we observed increased sensitization and deficient habituation to repetitive sensory stimuli consistent with drug overuse. The renin–angiotensin system in the brain seems to play a relevant role in neural plasticity and dependence behavior. We therefore sought differences in SSEP sensitization and habituation in patients with MOH who underwent angiotensin converting enzyme (ACE) I/D polymorphism analysis. Methods We recorded median-nerve SSEPs (two blocks of 100 sweeps) in 43 patients with MOH. We measured N20–P25 amplitudes, and assessed sensitization using the first block amplitudes, and habituation using amplitude changes between the two sequential blocks. According to their genotype, subjects were divided into three groups: “D/D”, “D/I” and “I/I” carriers. Results The habituation slope of the two SSEP block amplitudes was significantly increased in the D/D subgroup (n = 16) with respect to that of the I/I subgroup (n = 6), with the D/I subgroup (n = 21) falling in between. In D/D carriers, the habituation slope correlated positively with the duration of the overuse headache, and the first SSEP block amplitudes, a measure of sensitization, increased in strict relationship with the type of overused medication in the MOH patients overall and in the D/D subgroup; this was not so in the D/I and I/I subgroups. Conclusion In patients with MOH, the homozygote D/D ACE polymorphism influences habituation and sensitization to repeated sensory stimuli in strict relationship with medication overuse. We suggest that angiotensin peptides influence neuronal mechanisms of plasticity by interacting with central monoaminergic synaptic transmission.

Myelinated retinal fibers in autosomal recessive spastic ataxia of Charlevoix-Saguenay

Background:  Myelinated retinal nerve fibers are considered a hallmark of autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS) in French Canadian patients. The demonstration of a worldwide distribution of this disease, as well as the almost invariable presence of a normal retina on fundoscopy in cases outside Canada, suggests that more quantitative methodologies are needed to assess the retina in ARSACS.