[From gene to disease; spastin and hereditary spastic paraparesis]. / Van gen naar ziekte; spastine en hereditaire spastische paraparese.

Hereditary spastic paraparesis (HSP) belongs to a group of genetically and clinically heterogeneous disorders characterised by progressive spasticity of the legs and hyperreflexia. A further clinical distinction is drawn between pure and complicated HSP depending on the presence of other neurological and non-neurological signs. HSP may be inherited either as autosomal dominant, recessive, or X-linked. Twenty-two loci have been identified and additional ones are envisaged. In autosomal dominant HSP, 11 loci (five genes) have been identified, the most prevalent of which is linked to chromosome 2p, coding for spastin, an ATPase belonging to the AAA family (acronym of 'ATPase associated with diverse cellular activities'). Spastin is a nuclear protein, present in neurons, but not in glial cells, and seems to be involved in microtubule dynamics. Nonsense and frameshift mutations result in a reduced amount of spastin.

Extended extradural spinal arachnoid cyst: an unusual cause of progressive spastic paraparesis.

A 15-year old girl presented with a slowly progressive spastic paraparesis since the age of 12. Creatine kinase was slightly increased. Muscle biopsy carried out during tendon surgery for severe toe-walking showed 'myopathic' changes. Subsequent neurological evaluation and radiological studies revealed a large extradural arachnoid cyst extending from the 11th thoracic vertebra to the first lumbar vertebra. Her condition improved after operation. The 'myopathic' features turned out to be the result of chronic spinal compression. MRI is the method of choice to examine patients with non-hereditary progressive spastic paraparesis. Muscle biopsy and tendon surgery should not be performed, without careful neurological examination.

Familial spastic paraplegia: evidence for a fourth locus.

Autosomal dominant familial spastic paraparesis (AD-FSP) is a genetically heterogeneous disorder of the central nervous system characterized by a progressive spasticity of the legs. One gene causing AD-FSP (FSP1) has recently been mapped to chromosome 14q, another gene (FSP2) to chromosome 2p, and a third gene (FSP3) to chromosome 15q. We now report a large Dutch family with AD-FSP without linkage to any of these chromosomes, providing evidence for a fourth locus (FSP4).

Motor neuron disease (amyotrophic lateral sclerosis) arising from longstanding primary lateral sclerosis.

Three men were initially diagnosed as having primary lateral sclerosis (PLS), but eventually developed amyotrophic lateral sclerosis (ALS) after 7.5, 9, and at least 27 years. Non-familial ALS and PLS might be different manifestations of a single disease or constitute completely distinct entities. The clinical diagnosis of PLS predicts a median survival that is four to five times longer than in ALS.

Clinically silent dysfunction of dorsal columns and dorsal spinocerebellar tracts in hereditary spastic paraparesis.

Hereditary spastic paraparesis (HSP) is a neurodegenerative disorder, of which progressive spastic paraparesis is the clinical hallmark. Given the neuropathological evidence of degeneration of pyramidal tracts, dorsal columns, and dorsal spinocerebellar tracts, it is surprising that sensory symptoms are so indistinct compared to motor symptoms. We investigated the involvement of peripheral conduction and spinal proprioceptive pathways by nerve conduction studies, somatosensory evoked potentials of the median and tibial nerves, and quantitative assessment of the vibration perception thresholds of the hands and feet respectively in 32 patients suffering from HSP and healthy control groups. We did not find peripheral conduction abnormalities in HSP patients. Log-transformed vibration perception thresholds of the feet were abnormal in 13/32 HSP patients and in 0/64 controls (p < 0.00001), while tibial nerve somatosensory evoked potentials were abnormal in 20/32 patients and in 1/17 controls (p = 0.00001). The values for the upper extremities were within normal limits for nearly all subjects. In the HSP group, the neurophysiological disturbances did not correlate significantly with duration or severity of the disease, when age was controlled for, except for median nerve SSEP latency, which was affected by severity (p = 0.0072). We conclude that neurophysiological methods detected proprioceptive, subclinical abnormalities in several HSP patients, which may reflect degeneration of the dorsal columns, and/or dorsal spinocerebellar tracts. Since we found no correlation with several disease variables, the fact that not all HSP patients displayed these abnormalities may be caused by anatomical variations in proprioceptive pathways, rather than by phenotypical heterogeneity.

Linkage of a new locus for autosomal dominant familial spastic paraplegia to chromosome 2p.

Autosomal dominant familial spastic paraplegia (AD-FSP) is a genetically heterogeneous neurodegenerative disorder characterized by a spasticity of the lower limbs. A locus causing AD-FSP (FSP1) has been previously mapped to chromosome 14q. We now report linkage of a second AD-FSP locus (FSP2) to chromosome 2p21-p24 in five of seven French families and one large Dutch pedigree. The analysis of recombination events and multipoint linkage place FSP2 within a 4 cM interval flanked by loci D2S400 and D2S367.

Pure hereditary spastic paraparesis: an exclusion map covering more than 40% of the autosomal genome.

Pure hereditary spastic paraparesis (HSP) is an upper motor neuron syndrome clinically characterized by slowly progressive weakness and spasticity of the legs. To determine the chromosomal location of the genetic defect, a five-generational Dutch family with autosomal dominant pure HSP was subjected to linkage studies. Analysis was carried out on 48 members spanning three generations, of whom 23 individuals are definitely affected. By screening the genome with a total of 167 microsatellite markers distributed over all autosomes, an exclusion map for HSP was constructed. Depending on the actual size of the human genome, our exclusion map covered between 40% and 65% of its autosomal length. Loci on chromosomes 1, 8, 13, 14, and 18 showed slightly positive lod scores. The areas around these loci were investigated more closely, but no conclusive evidence for, or against, linkage could be obtained.

Posterior tibial nerve somatosensory evoked potentials in slowly progressive spastic paraplegia: a comparative study with clinical signs.

Clinical and neurophysiological examinations were performed on seven patients with hereditary spastic paraplegia and on eight patients with primary lateral sclerosis. The results were compared with those obtained from a group of 39 control subjects. Prolonged latency times and decreased amplitudes of the posterior tibial nerve (PTN) somatosensory evoked potentials (SEPs) were found in the majority of the patients. The SEP changes occurred without sensory impairment or with loss of vibration sense only. There was no significant relation between the PTN SEP abnormalities and the severity of pyramidal signs for the whole patient group, nor longitudinally for the individual subjects. Analyses of PTN SEPs in patients suffering from slowly progressive spastic paraplegia (SP), therefore, seem to be a method to indicate a feature of spinal cord dysfunction that is not related to the severity of clinical signs. Considering the neuropathology of the spinal cord in SP patients, we furthermore argue that the ascending spinal pathway involved in conducting impulses for PTN SEPs probably uses other routes as well as the funiculus gracilis.

Hereditary spastic paraparesis. Clinical and genetic data from a large Dutch family.

A large Dutch family is presented with pure hereditary spastic paraparesis. Pedigree analysis indicates autosomal dominant inheritance with complete penetrance and possibly anticipation in successive generations. These observations may have implications for genetic studies. Linkage studies in this family have excluded more than 40% of the autosomal genome.

Autosomal recessive paraparesis with amyotrophy of the hands and feet.

We present 2 sibs with autosomal recessive spastic paraparesis and severe amyotrophy of the distal limb muscles. Elaborate neurophysiologic studies disclosed slight to moderate slowing of motor conduction, moderate to severe reduction of motor action potentials, denervation potentials, and increased distal motor latencies. This syndrome, not having been reported since the papers by Ormerod (5) in 1904 and Holmes (6) in 1905, constitutes another rare, benign, complicated form of hereditary spastic paraparesis.

SPECT, CT and MRI in a Turkish family with Huntington's disease.

A Turkish family with Huntington's disease documented on CT, MRI and SPECT is reported. Whereas in clinically definite cases CT and MRI are of limited value and SPECT does not add anything of value, in one asymptomatic subject SPECT showed moderate caudate nucleus hypoperfusion, underlining the hypothesis that SPECT may have a role in predicting Huntington's disease.

The neuropathology of hereditary spastic paraparesis.

Hereditary spastic paraparesis or Strümpell's disease is a genetically determined neurodegenerative disorder in which the signs and symptoms are predominant in the legs. Inheritance is usually autosomal dominant and in a minority recessive. Neuropathological study reveals a degeneration of the corticospinal tract decreasing from lower lumbar to cervical level and of posterior columns increasing from lumbar to upper cervical level as well as degeneration of the spinocerebellar tracts in approximately 50%. The nature of this nucleo-distal central axonopathy and clinicopathological discrepancy for posterior columns, as well as the limits of the pathological process are poorly understood.

The numb chin.

An apparently innocuous complaint such as a numb chin may be associated with malignant disease, either as heralding symptom or as a manifestation of metastasis. A series of 15 patients with numbness of the chin is presented in which a malignancy was diagnosed prior to the numbness. The numbness diminished or disappeared in 66% of the patients following either systemic chemotherapy or radiotherapy.

A Dutch family with autosomal dominant pure spastic paraparesis (Strümpell's disease).

Families with "pure" hereditary spastic paraparesis of late onset have rarely been reported. Since the original article by Strümpell in 1880, many "complicated" forms of the disorder have been reported, and the question as to whether a "pure" form exists still arises from time to time. We present a Dutch family with "pure" hereditary spastic paraparesis, involving 15 affected members in three generations. The mode of inheritance was autosomal dominant, with onset of clinical signs in the fourth or fifth decade. Severity of the disease was mild; only a few of them became chairbound in the end. There were no sensory symptoms. Mild sphincter disturbances were mentioned by six patients. A review of the reports on Dutch families is given and arguments in favour of the existence of "pure" hereditary spastic paraparesis are discussed.

The quinolinic acid hypothesis in Huntington's chorea.

In the central nervous system and particularly in the striatum of patients with Huntington's disease (HD) a dramatic cell loss can be observed. Animal models of HD are based on intrastriatal injection of excitatory amino acids (EAAs). Stimulation of EAA receptors for a prolonged period of time degenerates the cells on which the EAA receptors are located, a phenomenon known as excitotoxicity. Several categories of EAA receptors, viz. quisqualate, kainate and N-methyl-D-aspartate (NMDA), have been identified in the central nervous system. Interestingly, quinolinic acid, a metabolite of tryptophan along the kynurenine pathway, appeared to be an agonist on the NMDA receptor and a potent excitotoxin. Indications have been reported, although still controversial, for derangements in the formation of quinolinic acid to occur in the brains of patients with HD. Based on these studies the likeliness of a role for quinolinic acid in the etiology of HD is evaluated.