In vivo proton MR spectroscopy findings specific for adenylosuccinate lyase deficiency.

Adenylosuccinate lyase (ADSL) deficiency is an inherited metabolic disorder affecting predominantly the central nervous system. The disease is characterized by the accumulation of succinylaminoimidazolecarboxamide riboside and succinyladenosine (S-Ado) in tissue and body fluids. Three children presented with muscular hypotonia, psychomotor delay, behavioral abnormalities, and white matter changes on brain MRI. Two of them were affected by seizures. Screening for inborn errors of metabolism including in vitro high resolution proton MRS revealed an ADSL deficiency that was confirmed genetically in all cases. All patients were studied by in vivo proton MRS. In vitro high resolution proton MRS of patient cerebrospinal fluid showed singlet resonances at 8.27 and 8.29 ppm that correspond to accumulated S-Ado. In vivo proton MRS measurements also revealed a prominent signal at 8.3 ppm in gray and white matter brain regions of all patients. The resonance was undetectable in healthy human brain. In vivo proton MRS provides a conclusive finding in ADSL deficiency and represents a reliable noninvasive diagnostic tool for this neurometabolic disorder.

Clinical, biochemical, neuropathological and molecular findings of the first Polish case of adenylosuccinase deficiency.

Adenylosuccinase (ADSL) deficiency is an autosomal recessive disorder affecting mainly the nervous system. The disease causes psychomotor retardation, frequently with autistic features and epilepsy. ADSL deficiency may be diagnosed by detection of two abnormal metabolites in body fluids--succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr). It is assumed that the former metabolite is neurotoxic. We present clinical, biochemical and neuropathological findings of a child affected by a severe form of ADSL deficiency. She had progressive neurological symptoms that started immediately after birth and died at 2.5 months of age. Macroscopically the brain showed signs of moderate atrophy. Histological examination of all grey matter structures showed widespread damage of neurons accompanied by microspongiosis of neuropile. Cerebral white matter showed lack of myelination in the centrum semiovale and diffuse spongiosis of neuropile. Myelination appropriate for the age was visible in posterior limb of internal capsule, in striatum, thalamus and in brain stem structures but diffuse destruction of myelin sheets was seen with severe marked astroglial reaction with signs of destruction of the cells and their processes. Ultrastructural examination showed enormous destruction of all cellular elements, but astonishingly mitochondria were relatively spared. The neuropathological changes can be considered as the neurotoxic result of metabolic disturbances connected with adenylosuccinase deficiency.

Adenylosuccinate lyase deficiency--first British case.

A deficiency of adenylosuccinate lyase (ASDL) is characterised by the accumulation of SAICAriboside (SAICAr) and succinyladenosine (S-Ado) in body fluids. The severity of the clinical presentation correlates with a low S-Ado/SAICAr ratio in body fluids. We report the first British case of ADSL deficiency. The patient presented at 14 days with a progressive neonatal encephalopathy and seizures. There was marked axial and peripheral hypotonia. Brain MRI showed widespread white matter changes. She died at 4 weeks of age. Concentrations of SAICAr and SAdo were markedly elevated in urine, plasma and CSF and the SAdo/SAICAr ratio was low, consistent with the severe phenotype. The patient was compound heterozygous for 2 novel ADSL mutations; c.9 G>C (A3P) and c.572 C>T (R190X).

Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: a report on three patients.

We report on the striking variable expression of adenylosuccinate lyase (ADSL) deficiency in three patients belonging to a family which originates from Portugal. ADSL deficiency is a rare autosomal recessive disorder of the de novo purine synthesis which results in accumulation of succinylpurines in body fluids. As a result, patients may have variable combinations of psychomotor retardation and/or regression, seizures, autistic features and cerebellar vermis hypoplasia. However, intrafamilial variable expression of the phenotype has not been documented to date in this disease and is not commonly observed in metabolic disorders. Here, while the proband had marked psychomotor regression and progressive cerebellar vermis atrophy, the other two affected patients presented mainly autistic features. Mutation analysis of the ADSL gene revealed the presence of a homozygous R426H mutation in this family. Finally, although ADSL deficiency is a rare disorder, this diagnosis should be considered and assessed using a simple urinary screening method for the presence of succinylpurines in any patient with mental retardation of unexplained origin.

Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency.

Adenylosuccinate lyase (ADSL) deficiency (MIM 103050) is an autosomal recessive inborn error of purine synthesis characterized by the accumulation in body fluids of succinylaminoimidazolecarboxamide (SAICA) riboside and succinyladenosine (S-Ado), the dephosphorylated derivatives of the two substrates of the enzyme. Because ADSL-deficient patients display widely variable degrees of psychomotor retardation, we have expressed eight mutated ADSL enzymes as thioredoxin fusions and compared their properties with the clinical and biochemical characteristics of 10 patients. Three expressed mutated ADSL enzymes (M26L, R426H and T450S) were thermolabile, four (A2V, R141W, R303C and S395R) were thermostable and one (del206-218), was inactive. Thermolabile mutations decreased activities with SAICA ribotide (SAICAR) and adenylosuccinate (S-AMP) in parallel, or more with SAICAR than with S-AMP. Patients homozygous for one of these mutations, R426H, displayed similarly decreased ADSL activities in their fibroblasts, S-Ado:SAICA riboside ratios of approximately 1 in their cerebrospinal fluid and were profoundly retarded. With the exception of A2V, thermostable mutations decreased activity with S-AMP to a much more marked extent than with SAICAR. Two unrelated patients homozygous for one of the thermostable mutations, R303C, also displayed a much more marked decrease in the activity of fibroblast ADSL with S-AMP than with SAICAR, had S-Ado:SAICA riboside ratios between 3 and 4 in their cerebrospinal fluid and were mildly retarded. These results suggest that, in some cases, the genetic lesion of ADSL determines the ratio of its activities with S-AMP versus SAICAR, which in turn defines the S-Ado:SAICA riboside ratio and the patients' mental status.