A new locus for autosomal recessive spastic paraplegia associated with mental retardation and distal motor neuropathy, SPG14, maps to chromosome 3q27-q28.

Hereditary spastic paraplegias (HSPs), a group of neurodegenerative disorders that cause progressive spasticity of the lower limbs, are characterized by clinical and genetic heterogeneity. To date, three loci for autosomal recessive HSP have been mapped on chromosomes 8p, 16q, and 15q. After exclusion of linkage at these loci, we performed a genomewide search in a consanguineous Italian family with autosomal recessive HSP complicated by mild mental retardation and distal motor neuropathy. Using homozygosity mapping, we obtained positive LOD scores for markers on chromosome region 3q27-q28, with a maximum multipoint LOD score of 3.9 for marker D3S1601. Haplotype analysis allowed us to identify a homozygous region (4.5 cM), flanked by markers D3S1580 and D3S3669, that cosegregates with the disease. These data strongly support the presence, on chromosome 3q27-28, of a new locus for complicated recessive spastic paraplegia, which we have named "SPG14."

Further evidence of a duplication in 17p11.2 in families with recurrence of HMSN Ia (Charcot-Marie-Tooth neuropathy type Ia).

Five Italian families with recurrence of cases of Charcot-Marie-Tooth disease (type Ia) were analysed using three closely linked DNA probes that detect polymorphisms in the region 17p11.2. The probe pVAW409R3 detected the presence of a duplication in all the affected subjects, but not in the subjects with normal electromyographic (EMG) findings. This observation confirms previous data indicating the association of the duplication with the disease, suggesting that, at least in populations of European origin, the duplication might be the molecular feature diagnostic of the pathological trait.

Genetic epidemiology of hereditary motor sensory neuropathies (type I).

Patients affected with hereditary motor sensory neuropathy (HMNS) type I were traced through hospital records. Each case was re-examined, a family history was drawn, and EMG examination was performed in those members of the family who could have inherited the trait. In the prevalence year 1987, in a population of 1,067,130 inhabitants of 2 contiguous provinces of northeast Italy, 100 living cases were recorded in 30 families, giving a minimal prevalence rate estimate of 9.37/100,000. HMSN I is inherited as an autosomal dominant trait, when clinical evaluation includes EMG. No difference may be established clinically between the 2 subtypes (Ia, linked to chromosome 1 and Ib, linked to chromosome 17). Sporadic cases are very rare and the mutation rate, including both the subtypes, is estimated between 3 and 6 X 10(-6).

X-linked Charcot-Marie-Tooth disease. A linkage study in a large family by using 12 probes of the pericentromeric region.

Linkage analysis was performed on 41 subjects belonging to a large family with a recurrence of X-linked Charcot-Marie-Tooth disease (CMTX), by using 12 restriction fragment length polymorphism markers mapping in p11-q13. The results are in agreement with previous linkage data. Three new markers that are potentially useful for genetic analysis of CMTX families are described. A more precise estimate of the localization of the disease locus was attempted by multipoint linkage analysis.

Serum lipids, lipoprotein analysis and apoprotein A-I, A-II and B levels in Friedreich's ataxia.

Serum lipid, lipoprotein and apoprotein parameters were evaluated in 15 patients (7 males and 8 females) with Friedreich's ataxia. Serum lipid levels in patients showed no significant differences compared to controls. Small reduction in serum phospholipid and in total HDL and HDL3 cholesterol levels were observed, and the female patients presented a slight reduced total cholesterol level; among the serum apoproteins, apo B was reduced only in the males. The most interesting findings concerned the lipoproteins, since both lipid and protein masses of the VLDL, LDL and HDL2 fractions were reduced. In reference to lipoprotein composition, however, HDL2 was the most modified fraction, showing an important protein reduction. From this point of view, this lipoprotein seems the most responsible for the changes observed in our patients. The meaning of this modified lipoprotein pattern in the pathophysiology of Friedreich's ataxia is not clear.

Evolution of cardiac involvement in progressive ophthalmoplegia with deleted mitochondrial DNA.

A 43-year-old woman with progressive external ophthalmoplegia developed a bifascicular block and dilatation of the right ventricle during 4 years of follow-up. Histochemical and electron microscopy studies detected mitochondrial abnormalities in ocular, skeletal muscle and cardiac biopsies. This case registers disease progression from the external ocular to the skeletal and cardiac muscles. Mitochondrial DNA was deleted in relation to the morphological abnormality.

Sensory-motor conduction time in amyotrophic lateral sclerosis.

19 ALS patients were submitted to motor evoked potentials (MEP) and F-wave from thenar muscles. Somatosensory evoked potentials (SEP) from median nerve were recorded as well in 16 patients. MEP were bilaterally absent in 4 patients (21%) and monolaterally absent in 6 patients (3.6%). Among patients with recordable waves, MEP and F-wave were significantly delayed. Their upper motor neuron conduction time was clearly abnormal only in one case. In SEP recordings the N9-N13 was significantly delayed, but the N13-N20 was normal. Four patients showed a combined sensory-motor dysfunction (increase of both N19-N13 interval and F-wave latency).

The role of life events in the myasthenia gravis outcome: a one-year longitudinal study.

We examined 51 patients suffering from myasthenia gravis (MG) and studied the relevance of stressful life events in relation to the course of the disease. Life events were assessed by means of the Paykel's Interview for Recent Life Events. The stage severity of MG was assessed by means of the Osserman and Genkins scale, twice per patient, at one year intervals. Simultaneously, life events were assessed for the 12 months preceding each of the 2 assessments of MG. Over the 2 MG evaluations 16 patients improved, 6 worsened and in 29 no change took place. Using life events data collected at the first interview, and applying a prospective design, no difference was found between patients who improved and those who remained unchanged or worsened. Life events reported at the second interview, as having occurred during the inter-assessment year, and collected according to a retrospective design, were significantly fewer in improvers than in non-improvers.

Psychiatric disturbances associated with myasthenia gravis.

Seventy-four myasthenic patients (54 F, 20 M; mean age 49.6 years) were evaluated using the diagnostic criteria of the DSM-III in order to investigate the prevalence of psychiatric disturbances in this order. Fifty-one had had thymectomies, of whom 28 females had hyperplasia, two females and five males had involution of the thymus, and 10 females and six males had thymomata. Psychiatric disturbances were observed in 38 subjects (51%), in particular, adjustment disorders with depressed mood and mixed emotional features (19%) (22% including adjustment disorder with anxious mood), affective disorders (13.5%) and personality disorders (18%).

Age-dependent requirements of cultured spinal cord neurons.

Biochemical response of spinal motor neurons (SMNs) to putative trophic factors present in the fetal calf serum (FCS) or released from the native glial cells was evaluated in ventral spinal cord cultures of 12- to 14- and 16- to 18-day embryos (before and after death of many SMNs in vivo) considering choline acetyltransferase and 2',3'-cyclic 3'phosphohydrolase as the biochemical markers of SMNs and oligodendrocytes respectively. Cultured SMNs of older embryos were more dependent than those of younger embryos on glial cells and on FCS putative trophic factors. FCS seemed more important than glial cells for survival of both older and younger SMNs and its withdrawal resulted in more prominent and longer neurite outgrowth. Our study demonstrates that the response of SMNs to trophic factors depends on the age of the rat embryos from which they were cultured.

Quantitative histopathology in congenital myopathies.

A histo-morphometric analysis has been carried out in 23 muscle biopsies obtained from patients with congenital myopathies (6 nemaline m., 10 centronuclear m., 4 central core m., 3 multicore m.) in order to improve diagnosis and to confirm the data available in literature. No relationship has been found between the severity of the disease and the histo-pathological features as previously described. Nevertheless, the following pathological aspects diverge from previous reports: a) the absence of rods within the nuclei and of mitochondrial abnormalities in nemaline myopathy; b) the presence of type I fiber hypertrophy and of mitochondrial alterations in 30% of the patients with centronuclear myopathy; c) the presence of cores even in type II fibers, mitochondrial abnormalities, nucleosis, inflammatory cellular reaction and fibrosis in addition to the absence of rods in central core myopathy; d) the type I fiber hypertrophy in all patients with multicore myopathy.

Correlation of ERG and pigment epithelium changes in external progressive ophthalmoplegia (EPO).

Six out of 17 patients with progressive external ophthalmoplegia (EPO) were found to have pigment anomalies with alterations in the electroretinographical (ERG) tracings. However, fluorangiography demonstrated alterations of the retinal pigment epithelium in patients with normal fundus and ERG examinations. We conclude that in our series there was no correlation between retinopathy and tapetoretinal degeneration.

Peroneal muscular atrophy with ataxia and partial myoclonic epilepsy.

Two brothers, 17 and 11 years old, presented with pes cavus, absence of deep tendon reflexes, péripheral vibratory sensory loss, ataxia, tremor, nystagmus, dysarthria and partial myoclonic epilepsy. Electromyography showed severe slowing of motor conduction velocity in the lower extremities and increased distal latencies. A peroneal nerve biopsy showed absence of myelin sheath in most fibres resulting in numerous demyelinated nerve fibres. The father and seven uncles on the paternal side had pes cavus, hammer toes and moderate vibratory peripheral sensory loss. Three of seven siblings had slow motor conduction velocities on EMG. None had EEG abnormalities. Epilepsy started at an early age in both patients with myoclonic jerks of the right arm especially during sleep. EEG recordings were characterized by focal or diffuse epileptiform discharges. In the elder brother a partial motor epileptic status occurred with adversive seizures involving the right side of the body. He died of a broncopneumonia after 3 days of this epileptic status. Histopathological examination showed a severe demyelination of dentato-rubral pathways in the cerebellum and a partial degeneration of Goll and Burdach's tracts in the cervical spinal cord. The nosological classification of this syndrome is discussed and an autosomal dominant inheritance with incomplete penetrance or variable expressivity is suggested.