Clinical features and molecular genetics of two Tunisian families with abetalipoproteinemia.

Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T>A, leading to a truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9+2T>G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins.

Clinical and molecular findings of ataxia with oculomotor apraxia type 2 (AOA2) in 5 Tunisian families.

Ataxia with oculomotor apraxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia caused by mutations in the SETX gene. It is a rare monogenic disease characterized by progressive cerebellar ataxia, oculomotor apraxia, axonal sensorimotor neuropathy, and an elevated serum α-fetoprotein level. To date, >100 AOA2 patients have been described and 75 different mutations in the SETX gene have been identified. We report here the clinical and genetic findings of 13 AOA2 patients from 5 unrelated Tunisian consanguineous families. DNA was collected from probands and available family members, and the 24 SETX exons were screened by direct sequencing. Four different homozygous SETX gene mutations were identified. The missense mutation 915G>T [W305C] has been described previously in Algeria. The 3 other SETX mutations are novel, including a missense mutation c.7231C>T [R 2380 W], a nonsense mutation c.6475 C>T [R2098X], and a deletion c.7180-7183delAAAA [D2332fsX2343]. More extensive screening by molecular genetic analysis of SETX in patients with Friedreich ataxia-like phenotype may show that AOA2 is more common in Tunisia than previously thought.

Spinal muscular atrophy due to double gene conversion event.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord. The survival motor neuron (SMN) gene has been identified as an SMA-determining gene. SMN exists as two copies in 5q13, and deletions in exons 7 and 8 of the telomeric copy (SMN(T)) occur in 95% of patients, regardless of disease severity. In a minority of patients, exon 7 but not exon 8 of SMN(T) appears deleted. We now report a patient with typical features of SMA type II who carried homozygous deletions of SMN(T) exon 7 and centromeric SMN (SMN(C)) exon 8 but retained SMN(T) exon 8 and SMN(C) exon 7. Sequence analysis demonstrated that SMN(C) exon 7 was adjacent to SMN(T) exon 8 on both SMN copies, indicating a double conversion. We confirm that sequence conversion is a common event in SMA and is associated with the milder form of the disease. The severity, however, can be modified in either positive or negative direction by other factors.