A natural history study of late onset spinal muscular atrophy types 3b and 4.

BACKGROUND: Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene plays a disease modifying role. SMA is classified into four different subtypes based on age of onset and clinical course (SMA types 1-4). The natural history of early onset SMA types 1-3a has been studied extensively. Late onset SMA is rare and disease course has not been studied in detail. OBJECTIVE: To perform a prospective study on the clinical course and the correlation with SMN2 copy numbers of late onset SMA. METHODS: Patients fulfilling the diagnostic criteria for late onset SMA (types 3b and 4) were included in the study. At inclusion and follow-up, muscle strength, respiratory function, functional status and quality of life were assessed. SMN2 copy number was determined in all patients. RESULTS: Twelve patients were identified and included. Six patients were siblings from one family, two patients were brothers from a second family and four patients were sporadic cases. All patients carried four copies of the SMN2 gene. Median age of disease onset was 22.2 years (10-37). Age of disease onset in patients from family one was lower as compared to the other patients. None of the outcome measures changed after a follow-up of 2.5 years. Five patients reported an increase in fatigue and muscle weakness. None of the patients showed symptoms of respiratory insufficiency. CONCLUSIONS: This study indicates that late onset SMA is not characterized by disease progression and that alternative or surrogate disease markers are required for the design of future trials. This study confirms the finding that SMN2 copy number is a SMA disease course modifier.

ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes.

SPAST mutations are the most common cause of autosomal dominant hereditary spastic paraplegias (AD-HSPs), but many spastic paraplegia patients are found to carry no mutations in this gene. In order to assess the contribution of ATL1 and REEP1 in AD-HSP, we performed mutational analysis in 27 SPAST-negative AD-HSP families. We found three novel ATL1 mutations and one REEP1 mutation in five index-patients. In 110 patients with sporadic adult-onset upper motor neuron syndromes, a novel REEP1 mutation was identified in one patient. Apart from a significantly younger age at onset in ATL1 patients and restless legs in some, the clinical phenotype of ATL1 and REEP1 was similar to other pure AD-HSPs.

MR spectroscopy findings in early stages of motor neuron disease.

BACKGROUND AND PURPOSE: Upper motor neuron degeneration varies in different phenotypes of MND. We used single-voxel MR spectroscopy of the primary motor cortex to detect corticomotoneuron degeneration and glial hyperactivity in different phenotypes of MND with a relatively short disease duration, contributing to further delineation of the phenotypes. MATERIALS AND METHODS: We prospectively included patients with ALS-B, ALS-L, and PMA and compared their data with those of patients with PLS and healthy controls. Each cohort consisted of 12 individuals. Disease duration was <1 year in ALS and PMA, but longer in PLS by definition. Follow-up examination was at 6 months. We measured ALSFRS-R, finger- and foot-tapping speed, and levels of the following: 1) NAAx, 2) mIns, and 3) Glx in the primary motor cortex. RESULTS: At baseline, we found significantly decreased NAAx levels and increased mIns levels in PLS. Levels of NAAx and mIns in patients with ALS-L and ALS-B were not significantly different from those in controls, but NAAx levels were significantly lower compared with those in PMA. At follow-up, only in PMA was a decrease of NAAx demonstrated. Glx levels varied widely in all groups. Levels of NAAx and mIns correlated well with clinical variables. CONCLUSIONS: Metabolite changes suggest neuronal dysfunction and active glial involvement in PLS. The corticomotoneuron is affected in early ALS-B and ALS-L, but at a later stage also in PMA. MR spectroscopy data are useful to obtain insight into the disease process at the level of the upper motor neuron in various phenotypes of MND.

Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes.

OBJECTIVE: To investigate the frequency of autosomal recessive paraplegin mutations in patients with sporadic adult-onset upper motor neuron (UMN) syndromes. METHODS: We analyzed the paraplegin gene in 98 Dutch patients with a sporadic adult-onset UMN syndrome. Inclusion criteria were a progressive UMN syndrome, adult onset, duration >6 months, and negative family history. Exclusion criteria were clinical or electrophysiologic evidence of lower motor neuron loss and evidence of other causes using a predefined set of laboratory tests, including analysis of the spastin gene. RESULTS: Seven patients had homozygous or compound heterozygous pathogenic paraplegin mutations: six patients had UMN symptoms restricted to the legs and one had UMN symptoms in legs and arms. No mutations were found in the 33 patients with UMN involvement of the bulbar region. Age at onset was lower in the seven patients with paraplegin mutations (37 years, range 34-42) than in the 91 patients without mutations (51 years, range 18-77, p = 0.001). Three of the seven patients with paraplegin mutations and none of the patients without mutations developed cerebellar signs during follow-up. CONCLUSIONS: Paraplegin mutations are a frequent cause of sporadic spastic paraparesis.

Primary lateral sclerosis as a phenotypic manifestation of familial ALS.

Primary lateral sclerosis (PLS) is a diagnosis of exclusion in patients with progressive spinobulbar spasticity and could be part of the clinical spectrum of ALS. Unlike ALS, which is familial in 5 to 10% of the cases, PLS has been described as a sporadic disorder in adults. The authors report two patients with PLS from unrelated SOD1-negative familial ALS families. These observations provide further evidence that PLS can be linked pathophysiologically to ALS.

Double-blind cross over treatment with mesterolone and placebo of subfertile oligozoospermic men value of testicular biopsy.

Fifty-nine carefully selected oligozoospermic men were randomly treated with mesterolone (75 mg/day) or placebo to improve fertility. After 6 months the medication was changed from mesterolone to placebo or vice versa. Fourteen pregnancies occurred, 7 under mesterolone and 7 under placebo. A testicular biopsy score was of prognostic value: the men who impregnated their partner had a significantly higher mean score than the men who did not fertilize. No other significant differences between these two groups of men were observed. Mesterolone had no significant influence other than placebo.

Motility and morphology of human spermatozoa in split ejaculates.

Sperm concentration and four motility characteristics (per cent motile spermatozoa, average velocity, average straight line approach and average speed constancy) were determined in three fractions of human split ejaculated from healthy volunteers. A semi-automatic analysis technique was used to determine sperm parameters from multiple exposure photographs (MEP). Sperm concentration and percentage motility were significantly higher in the first fraction as compared to the third fraction of split ejaculates. The average spermatozoal velocity, average speed constancy and average straight line approach were the same in all fractions. Differences in the percentage of motile spermatozoa were also found after collection of split ejaculates in culture medium. This phenomenon may have been caused by differences in sperm morphology. Significantly more normal spermatozoa were present in the first fractions of 19 split ejaculates as compared to the last fractions.