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Background Hyperargininemia due to mutations in ARG1 gene is an autosomal recessive inborn error of metabolism caused by a defect in the final step of the urea cycle. Common clinical presentation is a variable association of progressive spastic paraparesis, epilepsy, and cognitive deficits. Methods We describe the clinical history of an Italian child presenting progressive spastic paraparesis, carrying a new homozygous missense mutation in the ARG1 gene. A detailed clinical, biochemical, and neurophysiological follow-up after 7 months of sodium benzoate therapy is reported. Results Laboratory findings, gait abnormalities, spastic paraparesis, and electroencephalographic and neurophysiological abnormalities remained quite stable over the follow-up. Conversely, a mild cognitive deterioration has been detected by means of the neuropsychologic assessment. Conclusions Further longitudinal studies by means of longer follow-up and using clinical, biochemical, radiological, and neurophysiological assessments are needed in such patients to describe natural history and monitor the effects of treatments.

Background Neuronal death is often caused by an excess of glutamate that is maintained at physiological level by a non-autonomous cycle between glia and neurons called the glutamate-glutamine cycle. Aims It is possible to manipulate the activity of the enzymes that regulate the glutamate-glutamine cycle to ameliorate neuronal death? To answer this question we are taking advantage of Drosophila models used to dissect the cellular and molecular events of neurodegenerative disorders. Glutamate removal from the synaptic cleft by neuroglia is reduced in mouse models of Huntington’s disease (HD) and in HD patients. Results Our genetic and biochemical data suggest a key function for the enzyme Glutamine Synthetase-1 in ameliorating animal motility and neuronal loss in a Drosophila model for HD by inducing autophagy, a physiological process necessary to keep the neurons healthy by cleaning them from cellular debris and Huntingtin-protein aggregates. Methods We are using genetic and biochemical assays to understand how the metabolic components of the glutamate and glutamine catabolism, which are regulated by the activity of the enzymes Glutamine Synthetase, Glutamine Dehydrogenase and Glutaminase, affects autophagy in neuronal and glial cells, in normal and pathological conditions. In addition, we are preforming feeding experiments to understand if the assimilation of glutamine and glutamate might affect the viability and survival of the animals using a Drosophila model for HD. Conclusions Our preliminary results show that glutamine in the food increases animal life-span, both in wild-type and HD animals, while glutamate has the opposite effect.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessively inherited disorder of fatty acid metabolism due to ETFA, ETFB or ETFDH mutations. Riboflavin treatment ameliorates symptoms and metabolic profile in ETFDH-related MADD patients. We report on a 20-year-old boy with an 8-year history of progressive difficulty in walking, running and climbing stairs. Muscle biopsy showed a lipid myopathy and the acylcarnitine profile analysis was suggestive of MADD. Nevertheless, no evidence of molecular defects in the ETFA, ETFB and ETFDH exons or intron–exon boundaries was found. Treatment with riboflavin for 1 year resulted in a clear improvement in motor functions. Our report shows that some cases of MADD are not linked to ETFA, ETFB and ETFDH exon or intron–exon boundary changes. They could be due to quite rare promoter or deep intronic mutations or, most likely, to some unknown genetic defect. We therefore suggest to extend in these cases molecular studies to cDNA analysis and indicate the need of extensive pedigree studies to identify other possible disease-related loci. Most important, treatment of these cases with riboflavin can also be effective. Therefore, early diagnosis is essential to achieve the best treatment response.

Adult Refsum disease (ARD) is a progressive multisystem disorder that is characterized by retinitis pigmentosa, hearing and smell loss, skeletal deformities, and elevated levels of phytanic acid (PA) in tissues. Peripheral neuropathy, cardiac abnormalities, and skin ichthyosis are considered subsequent manifestations, and are often described in patients not treated with PA dietary restriction. Mutations of the gene encoding the phytanoyl-coenzyme A (CoA) hydroxylase enzyme (PHYH) are the major genetic cause of ARD,1 and in a small number of cases a second gene, PEX7, which encodes peroxin 7 receptor protein (PEX7), has been associated with the ARD phenotype.2 We observed two Italian siblings who presented with late-onset progressive ataxia and cognitive decline. They comprised a 56-year-old woman and her 63-year-old brother, born from consanguineous parents, and presented with infantile bilateral cataract and retinitis pigmentosa. Except for the visual defect, both siblings exhibited normal psychomotor development. In adulthood (at age 40 years for the brother and 53 years for the sister), both patients manifested progressive behavioral and cognitive abnormalities associated with ataxic gait. At the latest examination, at ages 57 and 63 years, respectively, they presented with dementia (Mini-Mental State Examination scores of 19/30 and 13/30, respectively), motor apraxia, ophthalmoparesis, mild dysarthria, ataxic gait, mild limb dysmetria, Babinski sign, and decreased lower-limb deep-tendon reflexes. Neither of the patients had hearing loss, anosmia, or short metacarpals/metatarsals, and only the brother presented with dilated cardiomyopathy. Brain MRI revealed mild diffuse atrophy, and muscle biopsy sampling revealed normal morphology. Nerve conduction studies demonstrated a mild motor demyelinating neuropathy in the lower limbs, and somatosensory evoked potentials revealed a prolongation of the central conduction time. Both patients also presented with increased plasma PA levels (387.5 and 188.9 µmol/L), suggesting a diagnosis of ARD. Mutational screening of PHYH was negative, but there was a novel homozygous mutation in PEX7, p.Leu12Pro, caused by a T>C transition at nucleotide 35 (c.35T>C). This missense variation involved a well-conserved residue, and has not been reported as a single-nucleotide polymorphism (SNP) in the Human Gene Mutation Database, National Center for Biotechnology Information database for SNPs (dbSNP132ver) or Exome Variant Server. In silico analyses predicted the mutation as probably damaging: the scores were 0.98 (PolyPhen-2-HumDiv), 0.635 (PolyPhen-2-HumVar), and 0 (Sorting Tolerant From Intolerant). The parents were not available for segregation analysis, and an asymptomatic brother was found to be heterozygous for this mutation. The patients refused a skin biopsy procedure, preventing investigations of plasmalogen synthesis.3 PEX7 mutations are most frequently found in infants affected by rhizomelic chondrodysplasia punctata type 1 (RCDP1), a congenital and rapidly worsening syndrome that is characterized by rhizomelia, chondrodysplasia punctata, cataract, and severe growth and mental retardation.3 The protein encoded by PEX7, Pex7, is essential for peroxisomal delivery of matrix enzymes containing the peroxisomal targeting signal type 2 in the amino acid sequence, including the phytanoyl-CoA hydroxylase and the plasmalogen synthesis apparatus.4 In both RCDP1 and ARD, patients present with elevated PA levels due to either a defect in the peroxisomal import of the metabolic enzymes or a primary loss-of-function of the phytanoyl-CoA hydroxylase enzyme.4 Several PEX7 mutations have so far been described in association with the RCDP1 phenotype. Only eight patients with PEX7 mutations and the Refsum phenotype have been reported, and in all of these cases the presentation was consistent with the ARD phenotype with a mild disease course (Table 1).2,3,5 In the previously reported cases, the most frequent disease manifestations were retinopathy, cataract, anosmia, hearing loss, and neuropathy (Table 1). In the cases described herein, the ocular abnormalities were also the earliest signs, but neither anosmia nor deafness was observed, while in the fifth decade both siblings developed progressive signs of dementia and ataxia. It is known that the clinical severity of this disease is associated with the residual activities and reduced amounts of Pex7.3 In particular, functional and modeling analyses have demonstrated that missense mutations associated with a severe phenotype are located in within the β sheets, probably causing a disruption of the protein structure.3 The p.Leu12Pro mutation, unlike previous missense mutations, is not located on the WD-40 repeat motif in PEX7, and it can be hypothesized that a less adverse effect on protein structure-allowing correct folding and greater residual activity-can account for the mild phenotype in these two patients. Table 1 Clinical, biochemical, and genetic characteristics of the patients with PEX7 gene mutations associated with Refsum disease phenotype, including the cases described in this study and review of the literature