João Guimarães

G2019S LRRK2 mutation in French and North African families with Parkinson's disease

Mutations in LRRK2 were recently identified in autosomal dominant Parkinsons disease (PD), including the G2019S mutation. To evaluate its frequency, we analyzed 198 probands with autosomal dominant PD, mostly from France and North Africa. Surprisingly, the frequency in North African families (7/17, 41%) was greater than those from Europe (5/174, 2.9%). The clinical features in 21 patients, including 1 with a homozygous mutation, were those of typical PD, with lower Mini‐Mental State Examination scores. There were also 15 unaffected mutation carriers, aged 32 to 74 years. LRRK2 mutations appear to be a common cause of autosomal dominant PD, particularly in North Africa. Ann Neurol 2005;58:784–787

CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5

Thirty-four different loci for hereditary spastic paraplegias have been mapped, and 16 responsible genes have been identified. Autosomal recessive forms of spastic paraplegias usually have clinically complex phenotypes but the SPG5, SPG24 and SPG28 loci are considered to be associated with pure forms of the disease. Very recently, five mutations in the CYP7B1 gene, encoding a cytochrome P450 oxysterol 7-alpha hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exon-intron boundaries of the CYP7B1 gene by direct sequencing in a series of 82 unrelated autosomal recessive hereditary spastic paraplegia index patients, manifesting either a pure (n = 52) or a complex form (n = 30) of the disease, and in 90 unrelated index patients with sporadic pure hereditary spastic paraplegia. We identified eight, including six novel, mutations in CYP7B1 segregating in nine families. Three of these mutations were nonsense (p.R63X, p.R112X, p.Y275X) and five were missense mutations (p.T297A, p.R417H, p.R417C, p.F470I, p.R486C), the last four clustering in exon 6 at the C-terminal end of the protein. Residue R417 appeared as a mutational hot-spot. The mean age at onset in 16 patients was 16.4 +/- 12.1 years (range 4-47 years). After a mean disease duration of 28.3 +/- 13.4 years (10-58), spasticity and functional handicap were moderate to severe in all cases. Interestingly, hereditary spastic paraplegia was pure in seven SPG5 families but complex in two. In addition, white matter hyperintensities were observed on brain magnetic resonance imaging in three patients issued from two of the seven pure families. Lastly, the index case of one family had a chronic autoimmune hepatitis while his eldest brother died from cirrhosis and liver failure. Whether this association is fortuitous remains unsolved, however. The frequency of CYP7B1 mutations were 7.3% (n = 6/82) in our series of autosomal recessive hereditary spastic paraplegia families and 3.3% (n = 3/90) in our series of sporadic pure spastic paraplegia. The recent identification of CYP7B1 as the gene responsible for SPG5 highlights a novel molecular mechanism involved in hereditary spastic paraplegia determinism.

Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 portuguese ataxia families

The spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. To date, eight different loci causing SCA have been identified: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA6, SCA7, and dentatorubropallidoluysian atrophy (DRPLA). Expansion of a CAG repeat in the disease genes has been found in five of these disorders. To estimate the relative frequencies of the SCA1, DRPLA, MJD, SCA2, and SCA6 mutations among Portuguese ataxia patients, we collected DNA samples from 48 ataxia families and performed polymerase chain reaction (PCR) amplification of the CAG repeat mutations on chromosomes 6p, 12p, 14q, 12q, and 19p, respectively. Fifty-five individuals belonging to 34 dominant families (74%) had an expanded CAG repeat at the MJD gene. In five individuals from two kindreds with a dominant pattern of inheritance (4%), an expanded CAG repeat at the SCA2 gene was found. In MJD patients, the normal allele size ranged from 13 to 41, whereas the mutant alleles contained 65 to 80 repeats. For the SCA2 patients, normal alleles had 22 or 23, while expanded alleles had between 36 and 47 CAG units. We did not find the SCA1, DRPLA, or SCA6 mutations in our group of families. The MJD mutation remains the most common cause of SCA in Portugal, while a small number of cases are caused by mutations at the SCA2 gene, and 22% are due to still unidentified genes.

Association of Huntington's disease and schizophrenia-like psychosis in a Huntington's disease pedigree

BackgroundHuntingtons disease (HD) is a dominantly inherited, neurodegenerative disorder due to expansion of a polymorphic trinucleotide repeat in the short arm of chromosome 4. Clinical manifestations consist of a triad of choreic movements, cognitive decline and psychiatric syndromes starting in the fourth to fifth decade. Psychiatric manifestations vary and may precede motor and cognitive changes. Personality changes and depression occur most commonly. Paranoid schizophrenia-like symptoms occur in 6% to 25% of cases.Case reportWe describe a 55 year-old woman with an 8 yearlong history of behavioural changes, multi-thematic delusions and auditory hallucinations. History and mental state examination were suggestive of paranoid schizophrenia. Neurological examination revealed discrete, involuntary movements affecting her arms and trunk. Genotyping detected an expanded allele (43 trinucleotide repeats). A three-generation-long family history of chorea and schizophrenia-like psychosis was found.ConclusionHD-families have been reported in which schizophrenia-like syndromes emerged in all or most HD-affected members long before they developed extra-pyramidal or cognitive changes. This has been attributed to more than mere coincidence. We hypothesise that in these families the HD gene is transmitted along with a low load of small-effect psychosis genes which, in the presence of the severe cognitive changes of HD, manifest as a schizophrenia-like phenotype. Further research is needed in order to clarify the links between genetic loading and the emergence of psychotic symptoms in Huntingtons disease.

New parkin mutations and atypical phenotypes in families with autosomal recessive parkinsonism.

The frequency of parkin mutations was evaluated in 30 families of highly diverse geographic origin with early-onset autosomal recessive parkinsonism. Twelve different mutations, six of which were new, were found in 10 families from Europe and Brazil. Patients with parkin mutations had significantly longer disease duration than patients without the mutation but with similar severity of disease, suggesting a slower disease course. Two patients with parkin mutations had atypical clinical presentation at onset, with predominant tremor when standing.

Genetic heterogeneity in hypokalemic periodic paralysis (hypoPP)

Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder belonging to a group of muscle diseases known to involve an abnormal function of ion channels. The latter includes hypokalemic and hyperkalemic periodic paralyses, and non-dystrophic myotonias. We recently showed genetic linkage of hypoPP to loci on chromosome 1q31-32, co-localized with the DHP-sensitive calcium channel CACNL1A3. We propose to term this locus hypoPP-1. Using extended haplotypes with new markers located on chromosome 1q31-32, we now report the detailed mapping of hypoPP-1 within a 7 cM interval. Two recombinants between hypoPP-1 and the flanking markers D1S413 and D1S510 should help to reduce further the hypoPP-1 interval. We used this new information to demonstrate that a large family of French origin displaying hypoPP is not genetically linked to hypoPP-1. We excluded genetic linkage over the entire hypoPP-1 interval showing for the first time genetic heterogeneity in hypoPP.

Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal

Background and purpose:u2002 The relative frequency of the different autosomal dominant cerebellar ataxia (ADCA) varies widely amongst different geographic locations. Here we describe a series of 45 ADCA families from Portugal.

Obsessive-compulsive symptoms in primary focal dystonia: A controlled study†‡§

Primary focal dystonia is an idiopathic neurological disorder causing involuntary muscle contraction. Its pathophysiology probably involves the basal ganglia and cortical‐basal pathways. Primary dystonia appears to be associated with significant obsessive‐compulsive symptoms, but evidence remains scarce and contradictory. We addressed the following research questions: (1) Do primary dystonia patients have high obsessive‐compulsive symptom scores? (2) Are these symptoms more severe in dystonia than in controls with equivalent peripheral neurological disorders? and (3) Is psychopathology different in botulinum toxin‐treated and ‐untreated dystonia patients? This work was a cross‐sectional, descriptive, controlled study comprising 45 consecutive patients with primary focal dystonia (i.e., blepharospasm, spasmodic torticollis, or writers cramp) 46 consecutive patients with hemifacial spasm, cervical spondylarthropathy, or carpal tunnel syndrome, and 30 healthy volunteers. Assessment included the DSM‐IV based psychiatric interview, Symptom Checklist 90R, Yale‐Brown Obsessive‐Compulsive Scale and Checklist, and the Unified Dystonia Rating Scale. Dystonia patients had higher Yale‐Brown Obsessive‐Compulsive Symptom scores than both control groups. Dystonia patients with obsessive‐compulsive symptom scores above cut‐off for clinical significance predominantly developed hygiene‐related symptoms. Major depression and generalized anxiety disorder were the most frequent psychiatric diagnoses in primary focal dystonia. Obsessive‐compulsive disorder frequency was 6.7%. Primary focal dystonia patients have higher obsessive‐compulsive symptom scores than individuals with similar functional disabilities resulting from other neurological disorders, suggesting that obsessive‐compulsive symptoms in dystonia are not reactive to chronic disability. Dystonic muscle contractions and obsessive‐compulsive symptoms may share a common neurobiological basis related to cortical‐basal dysfunction. Psychopathology, especially obsessive‐compulsive symptoms, should be actively explored and treated in primary focal dystonia.

Set-shifting and behavioral dysfunction in primary focal dystonia.

The occurrence of cognitive and behavioral symptoms in patients with primary dystonia remains a matter of debate. We compared 45 patients with primary dystonia with 27 control subjects for performance on neuropsychological tasks with a load on executive‐Wisconsin Card Sorting Test (WCST) and Stroop test, and visuospatial‐Bentons visual retention test (BVRT) and Block assembly test from Wechsler Adult Intelligence Scale BAT‐functions, as well as for intensity of obsessive‐compulsive symptoms (Yale Brown Obsessive Compulsive Scale, Y‐BOCS). Correlation analysis was performed between neuropsychological performance, dystonia characteristics (duration, age of onset) and severity (Unified Dystonia Rating Scale, UDRS), and Y‐BOCS. Patients made more perseverative errors on the WCST (P = 0.042) and had a higher mean Y‐BOCS (P = 0.003) score than controls. Timed tests (BVRT, BAT, Stroop test) correlated with UDRS. Y‐BOCS, WCST, and UDRS scores were not significantly correlated with one another.These results suggest that patients with primary dystonia may have set‐shifting deficits and a higher intensity of obsessive compulsive symptoms when compared to healthy subjects. This may reflect a pattern of complex neurophysiological dysfunction involving dorsolateral, orbitofrontal, and motor frontostriatal circuits.

Arachnoid cyst in a patient with psychosis: Case report

BackgroundThe aetiology of a psychotic disturbance can be due to a functional or organic condition. Organic aetiologies are diverse and encompass organ failures, infections, nutritional deficiencies and space-occupying lesions. Arachnoid cysts are rare, benign space-occupying lesions formed by an arachnoid membrane containing cerebrospinal fluid (CSF). In most cases they are diagnosed by accident. Until recently, the coexistence of arachnoid cysts with psychiatric disturbances had not been closely covered in the literature. However, the appearance of some references that focus on a possible link between arachnoid cysts and psychotic symptoms has increased the interest in this subject and raised questions about the etiopathogeny and the therapeutic approach involved.Clinical presentationWe present the clinical report of a 21-year-old man, characterised by the insidious development of psychotic symptoms of varying intensity, delusional ideas with hypochondriac content, complex auditory/verbal hallucinations in the second and third persons, and aggressive behaviour. The neuroimaging studies revealed a voluminous arachnoid cyst at the level of the left sylvian fissure, with a marked mass effect on the left temporal and frontal lobes and the left lateral ventricle, as well as evidence of hypoplasia of the left temporal lobe. Despite the symptoms and the size of the cyst, the neurosurgical department opted against surgical intervention. The patient began antipsychotic therapy and was discharged having shown improvement (behavioural component), but without a complete remission of the psychotic symptoms.ConclusionIt is difficult to be absolutely certain whether the lesion had influence on the patients psychiatric symptoms or not.However, given the anatomical and neuropsychological changes, one cannot exclude the possibility that the lesion played a significant role in this psychiatric presentation. This raises substantial problems when it comes to choosing a therapeutic strategy.