M. T. Dotti

A Rett syndrome MECP2 mutation that causes mental retardation in men

Objective: To characterize the clinical features of a new type of X-linked mental retardation associated with MECP2 mutation in the index family. Background: MECP2 mutations, originally described in a high percentage of patients with classic Rett syndrome, were considered lethal in men. The authors recently described a novel A140V MECP2 missense mutation in an Italian family with X-linked semidominant mental retardation. Methods: The neurologic features of six symptomatic relatives (two women and four men) carrying the mutation were compiled. Laboratory investigations included EEG, EMG, conduction velocity (CV) of peripheral nerves, brain MRI, and 1H-MR spectroscopy. Results: Mental retardation and signs of neurologic impairment were present in all the affected members, but more pronounced in men. Neurologic features included slowly progressive spastic paraparesis/pyramidal signs (6/6), distal atrophy of the legs (6/6), ataxia (2/6), and postural tremor of the hands (3/6). Speech was preserved (6/6) but was dysarthric in the oldest brothers (2/6). Mild dysmorphic features were present in all cases. Conclusion: The neurologic disorder associated with A140V MECP2 mutation is not necessarily lethal in men, but they are more severely affected than women of the same family.

Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients

Objective: To report the characteristics of patients suspected to have cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) but in whom no NOTCH3 gene pathogenic mutation was found. Methods: Between 2002 and 2008, we performed NOTCH3 gene analysis (exons 2–23) in 81 probands because CADASIL was clinically suspected. A retrospective analysis and comparison of clinical, familial, and neuroimaging features of patients with and without pathogenic mutations was performed. Results: CADASIL was diagnosed in 16/81 (20%) probands by finding a mutation leading to a cysteine substitution within the epidermal growth factor (EGF)–like repeats of the NOTCH3 receptor. In the remaining 65 patients, no pathogenic mutation was found. Some features were significantly (Fisher exact test p < 0.05) more frequent in CADASIL than in NOTCH3-negative patients: history of migraine (73 vs 39%), stroke before the age of 60 among relatives (71 vs 32%), severe leukoencephalopathy (94 vs 62%), white matter changes extended to the anterior temporal lobes (93 vs 45%), external capsule involvement (100 vs 50%), and presence of lacunar infarcts (100 vs 65%). The frequency of vascular risk factors was balanced between the 2 groups. No feature was peculiar to either group. Conclusions: Although certain clinical and neuroimaging features are more frequent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) than in NOTCH3-negative patients, none is pathognomonic. Clinicians should be aware that when diagnosing CADASIL, a number of patients with a cerebral disease phenotypically similar to CADASIL emerge. The genetic profile of these diseases and the full phenotypic difference with CADASIL remain to be further defined.

Brain structural damage in Friedreich’s ataxia

Objective: Neuropathological descriptions of the brain in Friedreich’s ataxia (FRDA) were obtained before availability of the current molecular genetic tests for this disease. Voxel-based morphometry (VBM) enables an unbiased whole-brain quantitative analysis of differences in gray matter (GM) and white matter (WM) volume. Methods: Using VBM, we assessed the brain structural damage in 22 patients with genetically confirmed FRDA and 25 healthy controls. The results were correlated with the disease duration and the severity of the patients’ clinical deficits—evaluated using the International Cerebellar Ataxia Rating Scale and Inherited Ataxia Clinical Rating Scale. Results: In patients with FRDA, VBM showed a symmetrical volume loss in dorsal medulla, infero-medial portions of the cerebellar hemispheres, the rostral vermis and in the dentate region. No volume loss in cerebral hemispheres was observed. The atrophy of the cerebellum and medulla correlated with the severity of the clinical deficit and disease duration. Conclusions: In patients with FRDA, significant GM and WM loss was observed only in the cerebellum and dorsal medulla. These structural changes correlate with the severity of the clinical deficit and disease duration.

BAEP changes in Leber's hereditary optic atrophy: further confirmation of multisystem involvement

A neurophysiological study of 11 patients belonging to 5 families affected by Lebers hereditary optic atrophy is reported. Electromyography, nerve conduction velocities and somatosensory evoked potentials were normal. Visual evoked potentials were absent or delayed, desynchronized and reduced in amplitude. Brainstem auditory evoked potentials were anomalous in 64% of subjects all without hearing defects. These changes which have never before been reported, confirm multisystem involvement in this disease.

Association of trisomy 9p and band heterotopia.

Article abstract Patients with the trisomy 9p syndrome and CNS abnormalities have been poorly assessed. We report a patient with trisomy 9p who showed band heterotopia on MRI. Abnormal neuronal migration is sufficiently frequent in patients with the trisomy 9p syndrome that brain MRI should be routinely considered in all patients with this syndrome.

Structural and metabolic brain abnormalities in preclinical cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy

Objective: To assess, by using quantitative MRI metrics, structural and metabolic brain abnormalities in subjects with preclinical cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Background: Brain MRI abnormalities have been occasionally reported in preclinical CADASIL subjects. However, very little is known as to when the brain tissue damage starts to accumulate, what brain regions are primarily involved and whether the brain damage is significant in subjects who have no overt clinical manifestations of the disease. Methods: Twelve subjects (mean age 40 years; range 26–55 years; males/females 6/6) with genetically proven CADASIL and no clinical signs of the disease underwent conventional MRI and proton MR spectroscopic imaging (1H-MRSI) to measure white matter (WM) lesion volume (LV), global and regional cerebral volumes, and WM levels of N-acetylaspartate (NAA) normalised to creatine (Cr). MR values were compared with those of 13 age- and sex-matched healthy controls. Results: All preclinical CADASIL showed WM lesions (range 0.2 to 26 cm3). They were mostly distributed in the frontal and parietal regions, with the highest probability in the corona radiata. On 1H-MRSI examination, NAA/Cr values were lower in preclinical CADASIL than in HC, particularly in the corona radiata (p<0.01). Normalised brain and cortical volumes were also lower in preclinical CADASIL than in HC (p<0.01), particularly in the frontal cortex. Conclusions: The pathological process occurring in CADASIL leads to damage of WM and neocortex much before the evidence of clinical symptoms. At this preclinical stage, this seems to take place prevalently in the frontal brain region.

Peripheral neuropathy in CADASIL

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary cerebral microangiopathy associated with mutations in the Notch 3 gene. The clinical phenotype is characterized by cerebral impairment even though typical microvascular changes are diffuse.ObjectiveTo assess peripheral neuropathy in patients with CADASIL.Patients and MethodsWe enrolled eleven CADASIL patients with variable phenotype including clinical signs of peripheral nerve involvement. In all patients electromyography and nerve conduction velocities were performed. Peripheral nerve biopsy was performed in three cases.ResultsWe found sensory motor neuropathy in 7/11 patients. Nerve biopsy revealed axonal and demyelinated findings.ConclusionOur findings suggest that peripheral neuropathy may be part of the CADASIL phenotype.

Normalisation of serum cholestanol concentration in a patient with cerebrotendinous xanthomatosis by combined treatment with chenodeoxycholic acid, simvastatin and LDH apheresis

Abstract. The concentrations of serum cholesterol, cholestanol and non–cholesterol sterols were measured in a patient with cerebrotendinous xanthomatosis under different therapeutic regimens. During treatment with chenodeoxycholic acid (CDCA) (750 mg/day) plus simvastatin (20 mg/day) for two years cholesterol and cholestanol concentrations averaged 188±10 mg/dl and 0.54±0.03 mg/dl. Thereafter treatment with simvastatin was discontinued. During treatment with low–density lipoprotein (LDL)–apheresis plus CDCA for 33 weeks, cholestanol concentrations reached almost normal levels (0.48±0.03 mg/dl immediately before and 0.32±0.02 mg/dl directly after LDL–apheresis, n=6). A further reduction of cholesterol and cholestanol was achieved by addition of simvastatin (20 mg/day). Cholesterol and cholestanol concentrations before and after LDL–apheresis during this treatment period averaged 122±4 mg/dl and 55±10 mg/dl, and 0.42±0.02 mg/dl and 0.18±0.06 mg/dl, respectively. Despite the consistent reduction of cholestanol to normal or even subnormal levels, a definite improvement of clinical symptoms was not noted. Our results suggest caution in the recourse to an aggressive cholestanol lowering therapy.

Clinical relevance and neurophysiological correlates of spasticity in cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease due to defective activity of sterol 27-hydroxylase, with plasma and tissue cholestanol storage. Clinical phenotype is characterized by both systemic manifestations and neurological signs. Therapy with chenodeoxycholic acid (CDCA) suppresses abnormal bile acid synthesis. The purpose of the study was to assess the frequency and clinical relevance of spasticity in the CTX phenotype and to study the usefulness of transcranial magnetic stimulation (TMS) in detecting corticospinal tract damage and monitoring the effects of replacement therapy. Twenty-four CTX patients underwent clinical evaluation including general disability scores, pyramidal and cerebellar function scales, assessment of serum cholestanol and TMS. Nine patients who started CDCA therapy at baseline received clinical and neurophysiological follow up. All patients showed signs of pyramidal damage which were relevant for clinical disability in 18 out of 24 cases (75%), resulting in spastic paraparesis. TMS revealed corticospinal alterations even in subjects with mild clinical signs of corticospinal tract involvement. After CDCA treatment, serum cholestanol decreased to normal concentrations in all patients. Clinical picture was unchanged in seven out of nine cases; in two others pyramidal signs disappeared. A reduction in abnormal neurophysiological parameters was found. Spastic paraparesis is the most frequent and relevant neurological feature in CTX patients. Replacement treatment with CDCA can prevent the progression of pyramidal damage, especially if started early in the course of the disease. TMS represents a sensitive indicator of corticospinal tract dysfunction and subclinical improvements in pyramidal function after CDCA therapy.

Four novel CYP27A1 mutations in seven Italian patients with CTX

Background and purpose:  Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, because of sterol 27‐hydroxylase deficiency. Clinical manifestations of CTX are tendon xanthomas, juvenile cataracts, osteoporosis, diarrhoea and multiple progressive neurological dysfunctions. More than 300 patients with CTX have been reported to date worldwide and about fifty different mutations identified in CYP27A1 gene. This study describes the clinical and laboratory findings of seven new patients.