Maria Anna Donati

Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa.

Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

A chaperone enhances blood α-glucosidase activity in Pompe disease patients treated with enzyme replacement therapy.

Enzyme replacement therapy is currently the only approved treatment for Pompe disease, due to acid α-glucosidase deficiency. Clinical efficacy of this approach is variable, and more effective therapies are needed. We showed in preclinical studies that chaperones stabilize the recombinant enzyme used for enzyme replacement therapy. Here, we evaluated the effects of a combination of enzyme therapy and a chaperone on α-glucosidase activity in Pompe disease patients. α-Glucosidase activity was analyzed by tandem-mass spectrometry in dried blood spots from patients treated with enzyme replacement therapy, either alone or in combination with the chaperone N-butyldeoxynojirimycin given at the time of the enzyme infusion. Thirteen patients with different presentations (3 infantile-onset, 10 late-onset) were enrolled. In 11 patients, the combination treatment resulted in α-glucosidase activities greater than 1.85-fold the activities with enzyme replacement therapy alone. In the whole patient population, α-glucosidase activity was significantly increased at 12 hours (2.19-fold, P = 0.002), 24 hours (6.07-fold, P = 0.001), and 36 hours (3.95-fold, P = 0.003). The areas under the curve were also significantly increased (6.78-fold, P = 0.002). These results suggest improved stability of recombinant α-glucosidase in blood in the presence of the chaperone.

Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro.

Caveolins are the principal protein components of caveolae, invaginations of the plasma membrane involved in cell signaling and trafficking. Caveolin-3 (Cav-3) is the muscle-specific isoform of the caveolin family and mutations in the CAV3 gene lead to a large group of neuromuscular disorders. In unrelated patients, we identified two distinct CAV3 mutations involving the same codon 78. Patient 1, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, shows an autosomal recessive mutation converting threonine to methionine (T78M). Patient 2, affected by isolated familiar hyperCKemia, shows an autosomal dominant mutation converting threonine to lysine (T78K). Cav-3 wild type (WT) and Cav-3 mutations were transiently transfected into Cos-7 cells. Cav-3 WT and Cav-3 T78M mutant localized at the plasma membrane, whereas Cav-3 T78K was retained in a perinuclear compartment. Cav-3 T78K expression was decreased by 87% when compared with Cav-3 WT, whereas Cav-3 T78M protein levels were unchanged. To evaluate whether Cav-3 T78K and Cav-3 T78M mutants behaved with a dominant negative pattern, Cos-7 cells were cotransfected with green fluorescent protein (GFP)-Cav-3 WT in combination with either mutant or WT Cav-3. When cotransfected with Cav-3 WT or Cav-3 T78M, GFP-Cav-3 WT was localized at the plasma membrane, as expected. However, when cotransfected with Cav-3 T78K, GFP-Cav-3 WT was retained in a perinuclear compartment, and its protein levels were reduced by 60%, suggesting a dominant negative action. Accordingly, Cav-3 protein levels in muscles from a biopsy of patient 2 (T78K mutation) were reduced by 80%. In conclusion, CAV3 T78M and T78K mutations lead to distinct disorders showing different clinical features and inheritance, and displaying distinct phenotypes in vitro.

Mutations in the cyclic adenosine monophosphate response element of the tyrosine hydroxylase gene

Tyrosine hydroxylase (TH) deficiency (OMIM 191290) is one cause of early‐onset dopa‐responsive dystonia. We describe seven cases from five unrelated families with dopa‐responsive dystonia and low homovanillic acid in cerebrospinal fluid who were suspected to suffer from TH deficiency. Analysis of part of the TH promotor showed five homozygous and two heterozygous mutations in the highly conserved cyclic adenosine monophosphate response element. Our data suggest that, if no mutations are found in the coding regions of the gene in patients strongly suspected of TH deficiency, the search for pathogenic mutations should be extended to regulatory promotor elements. Ann Neurol 2007

The suitability of the South Oaks Gambling Screen-Revised for Adolescents (SOGS-RA) as a screening tool: IRT-based evidence.

The South Oaks Gambling Screen-Revised for Adolescents (SOGS-RA) is one of the most widely used measures of adolescent gambling. We aimed to provide evidence of its suitability as a screening tool applying item response theory (IRT). The scale was administered to 981 adolescents (64% males; mean age = 16.57 years, SD = 1.63 years) attending high school. Analyses were carried out with a sample of 871 respondents, that is, adolescents who have gambled at least once during the previous year. Once the prerequisite of unidimensionality was confirmed through confirmatory factor analysis, unidimensional IRT analyses were performed. The 2-parameter logistic model was used in order to estimate item parameters (severity and discrimination) and the test information function. Results showed that item severity ranged from medium to high, and most of the items showed large discrimination parameters, indicating that the scale accurately measures medium to high levels of problem gambling. These regions of the trait were associated with the greatest amount of information, indicating that the SOGS-RA provides a reliable measure for identifying both problem gamblers and adolescents at risk of developing maladaptive behaviors deriving from gambling. The IRT-based evidence supports the suitability of the SOGS-RA as a screening tool in adolescent populations.

A mediation model to explain decision making under conditions of risk among adolescents: the role of fluid intelligence and probabilistic reasoning.

Aim: This study tested the mediating role of probabilistic reasoning ability in the relationship between fluid intelligence and advantageous decision making among adolescents in explicit situations of risk—that is, in contexts in which information on the choice options (gains, losses, and probabilities) were explicitly presented at the beginning of the task. Method: Participants were 282 adolescents attending high school (77% males, mean age = 17.3 years). We first measured fluid intelligence and probabilistic reasoning ability. Then, to measure decision making under explicit conditions of risk, participants performed the Game of Dice Task, in which they have to decide among different alternatives that are explicitly linked to a specific amount of gain or loss and have obvious winning probabilities that are stable over time. Results: Analyses showed a significant positive indirect effect of fluid intelligence on advantageous decision making through probabilistic reasoning ability that acted as a mediator. Specifically, fluid intelligence may enhance ability to reason in probabilistic terms, which in turn increases the likelihood of advantageous choices when adolescents are confronted with an explicit decisional context. Conclusions: Findings show that in experimental paradigm settings, adolescents are able to make advantageous decisions using cognitive abilities when faced with decisions under explicit risky conditions. This study suggests that interventions designed to promote probabilistic reasoning, for example by incrementing the mathematical prerequisites necessary to reason in probabilistic terms, may have a positive effect on adolescents’ decision-making abilities.

Neonatal onset of hyperornithinemia-hyperammonemia-homocitrullinuriasyndrome with favorable outcome

We report on a neonate with hyperammonemic coma in whom hyperornithinemia-hyperammonemia-homocitrullinuria syndrome was diagnosed. Appropriate treatment led to rapid clinical and metabolic improvement. The incorporation of 14C-ornithine on cultured fibroblasts confirmed the diagnosis. At the age of 18 months, the patient is in excellent clinical condition.

Lethal late onset cblB methylmalonic aciduria.

Objective To alert the physicians to the possibility of a late-onset inborn error of metabolism in an apparently previously healthy patient with acute clinical presentation. Design Case report. Setting Pediatric unit and general intensive care unit Patient An apparently previously healthy 12-yr-old female presented acutely with vomiting, fever, bronchopneumonia, and progressive loss of consciousness associated with ketoacidosis, hyperglycemia, and hyperammonemia. She died 3 days later with a diagnosis of insulin-dependent diabetes mellitus. Interventions Intravenous hydration, glucose and insulin, mechanical ventilation. Measurements and Main Results Organic acid analysis on a postmortem sample of aqueous humor revealed high levels of methylmalonic acid. Enzymatic studies on cultured fibroblasts were consistent with the diagnosis of cblB methylmalonic aciduria. Conclusions The diagnosis of cblB methylmalonic aciduria was made in a postmortem patient who died with a misdiagnosis of insulin-dependent diabetes mellitus. Unclear biochemical findings and positive family history should strongly lead to suspicion of an inborn error of metabolism in an apparently previously healthy critically ill patient.

Self-mutilation in a patient with mucolipidosis III

An 8-year-old girl with mucolipidosis III had self-mutilation of the distal phalanges of the second and third digits of her hands. She had neurophysiologic evidence of carpal tunnel syndrome, and consequent insensitivity to pain, which could explain the self-mutilation. Self-mutilation has not been previously described in lysosomal diseases in which carpal tunnel syndrome is frequently observed.