Aromatic L-Amino Acid Decarboxylase Deficiency: A Genetic Screening in Sicilian Patients with Neurological Disorders.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare autosomal recessive neurometabolic disorder caused by AADC deficiency, an enzyme encoded by the DDC gene. Since the enzyme is involved in the biosynthesis of serotonin and dopamine, its deficiency determines the lack of these neurotransmitters, but also of norepinephrine and epinephrine. Onset is early and the key signs are hypotonia, movement disorders (oculogyric crises, dystonia and hypokinesia), developmental delay and autonomic dysfunction. Taiwan is the site of a potential founder variant (IVS6+4A>T) with a predicted incidence of 1/32,000 births, while only 261 patients with this deficit have been described worldwide. Actually, the number of affected persons could be greater, given that the spectrum of clinical manifestations is broad and still little known. In our study we selected 350 unrelated patients presenting with different neurological disorders including heterogeneous neuromuscular disorders, cognitive deficit, behavioral disorders and autism spectrum disorder, for which the underlying etiology had not yet been identified. Molecular investigation of the DDC gene was carried out with the aim of identifying affected patients and/or carriers. Our study shows a high frequency of carriers (2.57%) in Sicilian subjects with neurological deficits, with a higher concentration in northern and eastern Sicily. Assuming these data as representative of the general Sicilian population, the risk may be comparable to some rare diseases included in the newborn screening programs such as spinal muscular atrophy, cystic fibrosis and phenylketonuria.

The Mitochondrial tRNASer(UCN) Gene: A Novel m.7484A>G Mutation Associated with Mitochondrial Encephalomyopathy and Literature Review.

Mitochondrial tRNASer(UCN) is considered a hot-spot for non-syndromic and aminoglycoside-induced hearing loss. However, many patients have been described with more extensive neurological diseases, mainly including epilepsy, myoclonus, ataxia, and myopathy. We describe a novel homoplasmic m.7484A>G mutation in the tRNASer(UCN) gene affecting the third base of the anticodon triplet in a girl with profound intellectual disability, spastic tetraplegia, sensorineural hearing loss, a clinical history of epilepsia partialis continua and vomiting, typical of MELAS syndrome, leading to a myoclonic epilepticus status, and myopathy with severe COX deficiency at muscle biopsy. The mutation was also found in the homoplasmic condition in the mother who presented with mild cognitive deficit, cerebellar ataxia, myoclonic epilepsy, sensorineural hearing loss and myopathy with COX deficient ragged-red fibers consistent with MERRF syndrome. This is the first anticodon mutation in the tRNASer(UCN) and the second homoplasmic mutation in the anticodon triplet reported to date.

De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms.

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

Refining analyses of copy number variation identifies specific genes associated with developmental delay.

Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.

Increased FGF3 and FGF4 gene dosage is a risk factor for craniosynostosis.

Interstitial duplications involving chromosome 11q have rarely been reported in the literature and mainly represent large, cytogenetically detectable rearrangements associated with a wide and variable spectrum of neurodevelopmental disorders. We report on a patient affected by intellectual disability, craniosynostosis, and microcephaly. Array-CGH analysis identified a de novo 290 kb interstitial duplication of chromosome 11q13.3 including the FGF3 and FGF4 genes. Clinical comparison of our patient with those previously reported with overlapping 11q duplications allows us to define the minimal duplicated region associated with craniosynostosis and strongly supports the hypothesis that the constitutional increased dosage of the FGF3 and FGF4 genes is a risk factor for craniosynostosis in humans.

The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

Pitt-Hopkins syndrome (PTHS) is characterized by severe intellectual disability, typical facial gestalt and additional features, such as breathing anomalies. Following the discovery of the causative haploinsufficiency of transcription factor 4 (TCF4), about 60 patients have been reported. We looked for TCF4 mutations in 63 patients with a suspected PTHS. Haploinsufficiency of TCF4 was identified in 14 patients, as a consequence of large 18q21.2 chromosome deletions involving TCF4 (2 patients), gene mutations (11 patients) and a t(14q;18q) balanced translocation disrupting TCF4 (one patient). By evaluating the clinical features of these patients, along with literature data, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combinations of the following characteristics: intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. Although PTHS is currently considered to be involved in differential diagnosis with Angelman and Rett syndromes, we found that combining the facial characteristics with a detailed analysis of both the physical and the neurological phenotype, made molecular testing for PTHS the first choice. Based on striking clinical criteria, a diagnosis of PTHS was made clinically in two patients who had normal TCF4. This report deals with the first series of PTHS patients of Italian origin.

Hypersensitivity to aromatic anticonvulsants: in vivo and in vitro cross-reactivity studies.

Aromatic antiepileptic drugs (phenytoin, carbamazepine, oxcarbazepine, and phenobarbital) are frequently associated with cutaneous eruptions. A cell-mediated pathogenic mechanism has been demonstrated in most of such reactions on the basis of positive responses to patch tests and/or lymphocyte transformation tests. Therefore, such tests are useful tools for evaluating anticonvulsant hypersensitivity reactions. Moreover, an in vitro lymphocyte toxicity assay, which exposes the patient's lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in a large percentage of patients with hypersensitivity reactions to aromatic anticonvulsants. Although several hypersensitivity reactions to sequential exposure to more than one aromatic anticonvulsant (i.e., clinical cross-reactivity) have been reported, there are few studies performed with patch tests and/or lymphocyte transformation tests assessing immunologic cross-reactivity, and their data are contradictory. In any case, considering studies performed in samples of at least 10 patients, the immunologic cross-reactivity rate among aromatic anticonvulsants appears to be low. On the other hand, the reported rate of the toxic cross-reactivity (i.e., assessed by lymphocyte toxicity assays) is high. Further in vivo and in vitro studies in large samples of subjects are needed to evaluate cross-reactivity among aromatic anticonvulsants.

Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins.

BACKGROUND: In patients with documented IgE-mediated hypersensitivity to penicillins, data on sensitization to cephalosporins vary. Administering cephalosporins to such patients is often deferred because of the risk for cross-reactivity. OBJECTIVE: To assess the cross-reactivity with cephalosporins and its potential determinants in patients with documented penicillin allergy. DESIGN: Prospective study in patients without clinical indications for cephalosporin treatment. SETTING: Italy. PATIENTS: 128 consecutive patients who sustained anaphylactic shock (n = 81) or urticaria (n = 47) and had positive results on skin tests for at least 1 of the penicillin reagents tested. MEASUREMENTS: All patients were skin tested with cephalothin, cefamandole, cefuroxime, ceftazidime, ceftriaxone, and cefotaxime. Patients with negative results for the last 4 cephalosporins were challenged with cefuroxime axetil and ceftriaxone. RESULTS: 14 patients (10.9% [95% CI, 6.1% to 17.7%]) had positive results on skin tests for cephalosporins, mostly for cephalothin or cefamandole. Skin test results for the minor determinant mixture were positive in 10 of 14 patients (71.4%) with cross-reactivity and 44 of 114 patients (38.6%) without cross-reactivity (odds ratio, 3.90 [CI, 1.17 to 13.40]; P = 0.0189). All 101 patients with negative results on skin tests for cefuroxime, ceftazidime, ceftriaxone, and cefotaxime tolerated cefuroxime axetil and ceftriaxone (tolerability rate, 100% [CI, 96.4% to 100%]). LIMITATIONS: Challenges were not followed by full therapeutic courses. Twenty-two patients declined challenges; positive responses in those patients would have decreased the tolerability rate to 82.1% (CI, 74.2% to 88.4%). CONCLUSIONS: These data confirm the advisability of avoiding cephalosporin treatment in patients with positive results on skin tests for penicillin. In patients who especially require cephalosporin treatment, we recommend skin tests with cephalosporins before assessing the tolerability of the cephalosporin with a graded challenge.

Effective prophylactic protocol in delayed hypersensitivity to contrast media: report of a case involving lymphocyte transformation studies with different compounds.

A patient with maculopapular reactions to iopamidol needed to undergo angiography for a cerebral arteriovenous malformation. In vivo and in vitro tests were performed with ionic and nonionic contrast media, including iopamidol and iobitridol. All results were positive, demonstrating delayed hypersensitivity. The patient received 6-alpha-methylprednisolone and cyclosporine 1 week before and 2 weeks after four angiograms were obtained with the use of iobitridol, which was well tolerated.

An updated survey on skin conditions in Down syndrome.

BACKGROUND: Only three not concordant surveys have been published on skin conditions associated with Down syndrome. OBJECTIVE: A sample ranging from infancy to adulthood, using acknowledged criteria for diagnosis, may highlight the skin involvement in Down syndrome. METHODS: We report the skin conditions observed in 203 people with Down syndrome, separated according to five different age ranges. We have set up two main groups of skin features: the phenotype and the dermatological diseases. RESULTS: The single palmar crease and xerosis are strongly represented within the phenotype. Among the dermatological diseases, folliculitis and syringomas have been observed mainly in adolescence and adulthood. Atopic dermatitis has been recognized in 10 subjects. Alopecia areata and milia-like idiopathic calcinosis cutis appeared in 6 subjects. CONCLUSION: People with Down syndrome suffer from peculiar dermatoses (syringomas, milia-like calcinosis, elastosis perforans serpiginosa). Other conditions (folliculitis, alopecia areata) are frequently observed.

Diagnosing nonimmediate reactions to penicillins by in vivo tests.

BACKGROUND: Maculopapular and urticarial rashes are nonimmediate manifestations common during penicillin treatment; the former often represent cell-mediated hypersensitivity. Our objectives were to assess the incidence of allergy in adults reporting nonimmediate manifestations during penicillin therapy and to evaluate the diagnostic potential of patch tests, delayed-reading skin tests and challenges in such cases. METHODS: We used prick and intradermal tests as well as patch tests with penicillin determinants, ampicillin, amoxicillin and any other suspect penicillins. We also performed challenges with the suspect antibiotics. RESULTS: Such antibiotics were aminopenicillins in 93.1% of 259 patients, most of whom had suffered from maculopapular rashes followed by piperacillin (4.2%). Three subjects displayed immediate skin test positivity. Ninety-four subjects showed patch test and delayed intradermal test positivity to the culprit penicillin (90 to aminopenicillins and 4 to piperacillin) and were considered as having had delayed hypersensitivity reactions. Five of the 8 subjects who displayed delayed intradermal test positivity and patch test negativity to the suspect penicillin underwent challenges, 2 reacted positively to the responsible aminopenicillin. Among the remaining 154 with negative results in allergologic tests, 125 agreed to undergo challenges; only 3 reacted. In all, 98 patients -- 93 of whom had experienced maculopapular rashes -- displayed delayed hypersensitivity (94 to aminopenicillins and 4 to piperacillin). CONCLUSIONS: Both patch and intradermal tests are useful in evaluating nonimmediate reactions to penicillins, particularly maculopapular rashes. Patch test and delayed intradermal positivity together indicate delayed hypersensitivity. Intradermal testing appears to be slightly more sensitive than patch testing.

Is there a relationship between zinc and the peculiar comorbidities of Down syndrome?

Zinc plays a central role in the immune system and has been found to be significantly reduced in people with Down syndrome. The effectiveness of zinc supplementation in people with Down syndrome has been reported with discordant results. A comparison was made between a range of clinical and biochemical variables and zinc levels in 120 individuals with Down syndrome. Two groups of participants, one with normal zinc levels and the second with low zinc levels, were compared on the following measures: growth hormone secretion, IgA and IgG antigliadin antibodies, presence of coeliac disease, T3, T4, fT3, fT4, TSH, hypothyroidism, hyperthyroidism, CD4/CD8 ratio, total immunoglobulins G and subclasses. No significant difference was found between the two groups, except for IgG4 which was, unexpectedly, significantly decreased in the group with normal zinc levels. In conclusion, an impairment of zinc blood level in individuals with Down syndrome does not necessarily impact on the organs and systems evaluated here.