Parents' experience of the communication process of positivity at newborn screening for metabolic diseases: A qualitative study.

BACKGROUND: The process of receiving a communication of positivity for metabolic diseases at expanded newborn screening (ENBS) is extremely articulated, involves a variety of actors (parents, maternal and child departments, clinical centres and laboratories) and is open to a variety of outcomes from false positive to true positive cases. Receiving communication of positivity can be highly stressful for parents and requires an adequate communication process to give clear and reliable information without causing excessive worry. This qualitative study describes the parents' experience of receiving a communication of positivity to metabolic diseases at ENBS, and their assessment of the quality of the communication process and steps, with the main aim to identify the process' strengths and weaknesses and to advance tailored recommendations to improve the communication process. METHOD: Fourteen in-depth, semi-structured phone interviews were conducted with parents whose children resulted positive to the ENBS. As part of the ENBS communication process, parents received a first phone call communication of positivity and a second in-person communication at metabolic clinical centres (MCC). The framework analysis method was used to organize the data and identify emerging themes. RESULTS: Parents were largely dissatisfied with the quality and depth of the information received and with the way the healthcare staff delivered the first communication phone call, which failed to create a caring, empathic and safe setting. Many parents tried to reduce the uncertainty by searching online information or consulting with other providers. Nevertheless, the majority of parents described the in-person visit at MCC as clear, welcoming and reassuring. CONCLUSION: More efforts are needed to improve the quality of the communication process of the ENBS. Guidelines, recommendations and standard scripts to communicate positivity are needed along with programmes and educational resources to train tailored communication skills.

Genotype and residual enzyme activity in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: Are predictions possible?

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common defect of mitochondrial ß-oxidation. Confirmation diagnostics after newborn screening (NBS) can be performed either by enzyme testing and/or by sequencing of the ACADM gene. Here, we report the results from enzyme testing in lymphocytes with gene variants from molecular analysis of the ACADM gene and with the initial acylcarnitine concentrations in the NBS sample. From April 2013 to August 2019, in 388 individuals with characteristic acylcarnitine profiles suggestive of MCADD the octanoyl-CoA-oxidation was measured in lymphocytes. In those individuals with residual activities <50%, molecular genetic analysis of the ACADM gene was performed. In 50% of the samples (195/388), MCADD with a residual activity ranging from 0% to 30% was confirmed. Forty-five percent of the samples (172/388) showed a residual activity >35% excluding MCADD. In the remaining 21 individuals, MCAD residual activity ranged from 30% to 35%. The latter group comprised both heterozygous carriers and individuals carrying two gene variants on different alleles. Twenty new variants could be identified and functionally classified based on their effect on enzyme function. C6 and C8 acylcarnitine species in NBS correlated with MCAD activity and disease severity. MCADD was only confirmed in half of the cases referred suggesting a higher false positive rate than expected. Measurement of the enzyme function in lymphocytes allowed fast confirmation diagnostics and clear determination of the pathogenicity of new gene variants. There is a clear correlation between genotype and enzyme function underlining the reproducibility of the functional measurement in vitro.

Pseudotumour cerebri associated with mycoplasma pneumoniae infection and treatment with levofloxacin: a case report.

BACKGROUND: Idiopathic intracranial hypertension (IIH), also known as pseudotumour cerebri syndrome (PTCS), is characterized by the presence of signs and symptoms of raised intracranial pressure without evidence of any intracranial structural cause and with normal cerebrospinal fluid microscopy and biochemistry. Obesity, various systemic diseases and endocrine conditions, and a number of medications are known to be risk factors for PTCS. The medications commonly associated with PTCS are amiodarone, antibiotics, corticosteroids, cyclosporine, growth hormone, oral contraceptives, vitamin A analogues, lithium, phenytoin, NSAIDs, leuprolide acetate, and some neuroleptic drugs. In relation to antibiotics, quinolones may cause intracranial hypertension, and most reported cases of quinolone-induced intracranial hypertension were associated with nalidixic acid, ciprofloxacin, ofloxacin, or pefloxacin. Literature reports of levofloxacin-induced PTCS are rare. Some authors recently hypothesized that Mycoplasma pneumoniae may trigger PTCS. CASE PRESENTATION: We report on a 14-year-old overweight White Italian boy who suffered headache, diplopia, and severe bilateral papilloedema after a Mycoplasma pneumoniae infection, exacerbated on levofloxacin intake. A spontaneous improvement in headache and a reduction in diplopia was seen during hospitalisation. Oral acetazolamide therapy led to the regression of papilloedema in about five months. No permanent eye damage has been observed in our patient to date. CONCLUSIONS: PTCS pathophysiology may be multifactorial and its specific features and severity may be a consequence of both constitutional and acquired factors interacting synergistically. It may be useful for paediatricians to know that some antibiotics may have the potential to precipitate PTCS in patients who already have an increased CSF pressure due to a transitory imbalanced CSF circulation caused by infections such as Mycoplasma pneumoniae, with headache being the first and most sensitive, but also the least specific, symptom.

Correction: The absence that makes the difference: choroidal abnormalities in Legius syndrome.

Correction to: Journal of Human Genetics advance online publication 27 July 2017; https://doi.org/10.1038/jhg.2017.78.

Identification of an atypical microdeletion generating the RNF135-SUZ12 chimeric gene and causing a position effect in an NF1 patient with overgrowth.

Neurofibromatosis type I (NF1) microdeletion syndrome, which is present in 4-11% of NF1 patients, is associated with a severe phenotype as it is caused by the deletion of NF1 and other genes in the 17q11.2 region. The variable expressivity of the disease makes it challenging to establish genotype-phenotype correlations, which also affects prognosis and counselling. We here describe a 3-year-old NF1 patient with an atypical deletion and a complex phenotype. The patient showed overgrowth, café au lait spots, inguinal freckling, and neurological abnormalities. The extent of the deletion was determined by means of array comparative genomic hybridisation, and its breakpoints were isolated by means of long-range polymerase chain reaction. Sequence analysis of the deletion junction fragment revealed the occurrence of an Alu-mediated recombination that led to the generation of a chimeric gene consisting of three exons of RNF135 and eleven exons of SUZ12. Interestingly, the deletion shares a common RNF135-centred region with another deletion described in a non-NF1 patient with overgrowth. In comparison with the normal RNF135 allele, the chimeric transcript was 350-fold over-expressed in peripheral blood, and the ADAP2 gene located upstream of RNF135 was also up-regulated. In line with this, the deletion causes the loss of a chromatin TD boundary, which entails the aberrant adoption of distal cis-acting regulatory elements. These findings suggest that RNF135 haploinsufficiency is related to overgrowth in patients with NF1 microdeletion syndrome and, for the first time, strongly indicate a position effect that warrants further genotype-phenotype correlation studies to investigate the possible existence of previously unknown pathogenic mechanisms.

The absence that makes the difference: choroidal abnormalities in Legius syndrome.

Neurofibromatosis type 1 (NF1) is an hereditary disorder characterized by abnormal proliferation of multiple tissues of neural crest origin, and presents mainly with multiple café-au-lait macules, axillary freckling and neurofibromas. Choroidal involvement in NF1 patients has been studied, thanks to the development of non-invasive tools such as infrared monochromatic light during fundus examination, which showed bright patchy lesions consistent with choroidal nodules. Choroidal abnormalities identified with near-infrared reflectance have reported with a frequency of up to 100% in NF1, and have been recently been proposed as a novel diagnostic criterion for NF1. Legius syndrome can be clinically indistinguishable from NF1 and results in a small percentage of individuals being misdiagnosed. We investigated the presence of choroidal abnormalities in Legius syndrome to determine their specificity to NF1 and their potential usefulness as a novel diagnostic criterion for NF1. We examined the fundus of 16 eyes by confocal scanning laser ophthalmoscopy with infrared monochromatic light in eight patients with molecularly confirmed Legius syndrome. No abnormalities were observed, confirming the diagnostic value of choroidal abnormalities for the diagnosis of NF1.

Muscle MRI of classic infantile pompe patients: Fatty substitution and edema-like changes.

INTRODUCTION: The aim of this study was to evaluate the muscle MRI pattern of 9 patients (median age: 6.5 ± 2.74 years) affected by classic infantile-onset Pompe disease who were treated with enzyme replacement therapy. METHODS: We performed and qualitatively scored T1-weighted (T1-w) sequences of the facial, shoulder girdle, paravertebral, and lower limb muscles and short-tau inversion recovery (STIR) sequences of the lower limbs using the Mercuri and Morrow scales, respectively. RESULTS: On T1-w images, mild (grade 1) or moderate (grade 2) involvement was found in the tongue in 6 of 6 patients and in the adductor magnus muscle in 6 of 9. STIR hyperintensity was detected in all areas examined and was categorized as limited to mild in 5 of 8 patients. CONCLUSIONS: On T1-w sequences, mild/moderate adipose substitution in the adductor magnus and tongue muscles was documented. STIR edema-like alterations of thigh and calf muscles are novel findings. Correlations with biopsy findings and clinical parameters are needed to fully understand these findings. Muscle Nerve 55: 841-848, 2017.

Deoxyguanosine kinase deficiency: natural history and liver transplant outcome.

Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.

Healthcare transition in patients with rare genetic disorders with and without developmental disability: neurofibromatosis 1 and Williams-Beuren syndrome.

There are between 5,000 and 8,000 distinct rare diseases (RDs) affecting 6-8% of the population, most of which are caused by genetic defects. Many are highly complex, childhood-onset, multi-system disorders that are often associated with developmental disability, and require lifelong, highly specialized care and support. As larger numbers of children with previously fatal RDs survive into adulthood, they encounter significant challenges in transitioning from family-centered, developmentally focused, multidisciplinary pediatric care to a less supportive adult healthcare system that is often unfamiliar with these conditions. This paper discusses the challenges of the transition from pediatric to adult health care in two groups of patients with multisystem genetic RDs (neurofibromatosis 1 [NF1] and Williams-Beuren syndrome [WBS]), and analyzes strategies for making the process easier for patients with and without developmental disabilities. Our findings show that there are still no guidelines in national healthcare programs on how to transition RD adolescents with and without developmental disabilities, and only a few pediatric centers have implemented the elements of transition in their general practice. Evidence regarding programs to facilitate transition is inconclusive and the transition from pediatric medicine to adult medicine for RDs remains a major challenge. However, transition requires both time and personnel, which are difficult to find in periods of fiscal austerity. Nevertheless, we should strongly advocate for governments investing more into transition infrastructure or they will face increased long-term social and economic costs due to poor treatment compliance, disengagement from services, increased genetic risks, and higher rates of disease-related complications.

Hyperammonemia Syndrome After Lung Transplantation: A Double-Hit Fatal Syndrome. A Case Report.

Hyperammonemia after lung transplantation is a rare but potentially fatal condition. A 59-year-old male patient affected by pulmonary fibrosis underwent an uncomplicated bilateral lung transplant. Fourteen days after the procedure, the patient developed severe encephalopathy caused by elevated serum ammonia levels. Ureaplasma parvum and Mycoplasma hominis were found on bronchial aspirate and urinary samples as well as on pharyngeal and rectal swabs. Despite the initiation of multimodal therapy, brain damage due to hyperosmolarity was so extensive to evolve into brain death. The autopsy revealed glutamine synthetase hypo-expression in the hepatic tissue. The pathophysiology of hyperammonemia syndrome in lung transplant recipients remains unclear. Previous studies have described the presence of disorders of glutamine synthetase, while others considered the infection with urea-splitting microorganisms as a cause of hyperammonemia syndrome. Our report describes the case of a patient who developed hyperammonemia after a lung transplant in which both the aforementioned etiologies were documented. A high level of clinical suspicion for hyperammonemia syndrome should be maintained in lung transplant recipients. Timely recognition and treatment are critical to prevent the potentially dreadful evolution of this severe complication.

A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy.

Pathogenic variants impacting upon assembly of mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) predominantly result in early onset mitochondrial disorders often leading to CNS, skeletal and cardiac muscle manifestations. The aim of this study is to describe a molecular defect in the COX assembly factor gene COX18 as the likely cause of a neonatal form of mitochondrial encephalo-cardio-myopathy and axonal sensory neuropathy. The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive developing in the first months of life. Serum lactate was consistently increased. Whole exome sequencing allowed the prioritization of the unreported homozygous substitution NM_001297732.2:c.667 G > C p.(Asp223His) in COX18. Patient's muscle biopsy revealed severe and diffuse COX deficiency and striking mitochondrial abnormalities. Biochemical and enzymatic studies in patient's myoblasts and in HEK293 cells after COX18 silencing showed a severe impairment of both COX activity and assembly. The biochemical defect was partially rescued by delivery of wild-type COX18 cDNA into patient's myoblasts. Our study identifies a novel defect of COX assembly and expands the number of nuclear genes involved in a mitochondrial disorder due to isolated COX deficiency.

Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and homocystinuria.

BACKGROUND: Inborn errors of cobalamin (Cbl) absorption and metabolism form a large group of rare diseases that include Cbl-C disorder. Among the renal complications of Cbl-C disorder, atypical hemolytic uremic syndrome (HUS) is the least common and has been described only in a small number of cases. CASE-DIAGNOSIS/TREATMENT: Four patients were admitted to our clinic after 15-30 days of life with vomiting associated with poor sucking, failure to thrive, lethargy and hypotonia. Examinations showed thrombocytopenia and microangiopathic hemolytic anemia associated with renal damage. The neonates had high blood homocysteine levels, increased urinary levels of both homocystine and methylmalonic acid, increased propionylcarnitine (C3) levels and an increased C3/acetylcarnitine ratio. Homozygosity for c.271-272dupA (p.Arg91LysfsX14) of the MMACHC gene was detected in three patients, and heterozygosity for c.271-272dupA and c.666C > A(p.Tyr222X) in one patient, which confirmed the diagnosis of Cbl-C disorder. Treatment with parenteral hydroxycobalamin in combination with folic acid and betaine gradually normalized the metabolic test findings and hematological and renal parameters after about 1 week. CONCLUSIONS: Atypical HUS in neonates with Cbl-C disorder may be associated with mild to moderate renal involvement also in early-onset disease, and early adequate therapy can reverse renal damage.

Severe vitamin B12 deficiency in an exclusively breastfed 5-month-old Italian infant born to a mother receiving multivitamin supplementation during pregnancy.

BACKGROUND: In infants, vitamin B12 deficiency may be due to an inborn error of absorption and metabolism, or nutritional problems. CASE PRESENTATION: An exclusively breastfed 5-month-old Italian male infant, who was born after a normal full-term pregnancy to a vegan mother who was apparently daily treated with a multivitamin oral preparation during the second and third trimester, was hospitalised because of poor weight gain, feeding difficulties, severe pallor, muscle hypotonia and somnolence. Upon admission, his weight, length and head circumference were below the third percentile, he had an enlarged liver and spleen, and showed a significant delay in developmental milestones and communicative reactions. He had a hemoglobin level of 4.7 g/dL with an MCV of 84.2 fL, a white blood cell count of 4,680/mm3, and a platelet count of 45,000/mm3. His serum vitamin B12 level was 57 pg/mL (normal value 180-500 pg/mL) and serum folate level 12.8 ng/mL (normal value >3 ng/mL). The results of metabolic examinations excluded a cobalamin C disorder, whereas nutritional screening showed a serum iron concentration of 9 µg/dL and serum ferritin of 4 ng/mL. Magnetic resonance imaging of the brain showed mild dilatation of the lateral ventricles with diffuse delayed myelination. The child was diagnosed as having vitamin B12 and iron deficiency due to nutritional inadequacy and was immediately treated with packed red blood cells, intramuscular vitamin B12 injections, and iron supplementation. A few days after the start of therapy, his hemoglobin levels and other hematological parameters rapidly improved, and a clinical improvement was observed within few weeks. There was an increase in his achievement of developmental milestones, but his development was still retarded seven months after the start of therapy. CONCLUSION: This case underlines the importance of adequately controlling maternal vitamin B12 intake during pregnancy by means of supplementation which, in the case of vegan mothers, should be significantly greater than that usually given. Moreover, the supplementation should be continued during lactation in order to avoid the development of signs of deficiency that may be associated with persistent neurological problems in infants. The case also highlights the need to consider vitamin B12 deficiency in infants with severe anemia even if their hematological parameters do not indicate megaloblastic anemia because the concomitant presence of substantial iron deficiency may modify the characteristics of the anemia.

CHARGE syndrome presenting with persistent hypoglycemia: case report and overview of the main genetic syndromes associated with neonatal hypoglycemia.

BACKGROUND: CHARGE syndrome (CS) is an autosomal dominant genetic condition whose recognition in the neonatal period is complicated by considerable phenotypic variability. Pediatric patients with genetic disorders have a known high incidence of hypoglycemia, due to many concurring factors. To date, neonatal hypoglycemia is a feature poorly explored in the literature associated with CS. This paper adds to the existing literature on hypoglycemia in CS and provides a brief review of the mechanisms through which CS, as well as the main genetic syndromes associated with neonatal hypoglycemia, may determine it. CASE PRESENTATION: The patient was a term newborn, first-born daughter to non-consanguineous parents. At birth, axial hypotonia with slight hypertonia of the limbs, and dysplastic auricles were noted. The incidental finding of asymptomatic hypoglycemia led to the initiation of glucose infusion on the II day of life, continued for a total of 8 days (maximum infusion rate: 8 mg/kg/min). In-depth endocrinological examinations showed poor cortisol response to the hypoglycemic stimulus, with normal GH values, thyroid function and ACTH. In view of the suspected hypoadrenalism, oral hydrocortisone therapy was initiated. Inappropriately low values of plasmatic and urinary ketones supported the hypothesis of concomitant transient hyperinsulinism, not requiring therapy. A brain MRI was performed, documenting thinning of the optic nerves, non-displayable olfactory bulbs and dysmorphic corpus callosum. An eye examination revealed bilateral chorioretinal coloboma. Temporal bone CT scan showed absence of the semicircular canals. The unexpected findings of coloboma and absence of semicircular canals led to the suspicion of CS, later confirmed by the molecular analysis of CHD7. CONCLUSIONS: It seems important to consider CS in the differential diagnosis of persistent hypoglycemia in newborns with specific anomalies. At the same time, it is advisable to consider the risk of hypoglycemia in children with CS, as well as other genetic syndromes. Awareness of the many possible causes of hypoglycemia in newborns with genetic conditions may help steer the investigations, allowing for an appropriate and timely treatment.

Immunogenicity, safety and tolerability of monovalent 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine in children and adolescents with Williams or Cornelia De Lange syndrome.

In some subjects with severe neurological diseases, a reduced immune response to seasonal influenza vaccine has been demonstrated. Patients with Williams or Cornelia de Lange syndrome frequently have abnormalities in neurodevelopment. This study has evaluated the immunogenicity, safety and tolerability of a monovalent 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine in these subjects. Eighteen patients with Williams syndrome (ten males; mean age ± standard deviation [SD] 12.74 ± 4.49 years), 11 with Cornelia de Lange syndrome (six males; mean age 12.90 ± 4.85 years) and 30 age- and gender-matched healthy controls (16 males; mean age 12.49 ± 4.55 years), never vaccinated against influenza, received a dose of the vaccine between 1 and 30 November 2009. Four weeks later, the seroconversion rates in the three groups were between 72% and 80% and the seroprotection rates were 100%, with a similar increase in antibody levels. Two months later, most of the subjects remained seroconverted with no statistically significant difference between the groups, and about 94% of the patients with Williams syndrome, all of those with Cornelia de Lange syndrome and all of the healthy controls were still seroprotected. Safety and tolerability were very good, with no difference between the groups. None of the patients developed documented influenza during the study period. These results show that the immunogenicity, safety, and tolerability of a single dose of the monovalent 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine in children and adolescents with Williams or Cornelia de Lange syndrome and moderate to severe mental disabilities is very good, and similar to that of healthy subjects.

PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations.

BACKGROUND: The role of epigenetics in inborn errors of metabolism (IEMs) is poorly investigated. Epigenetic changes can contribute to clinical heterogeneity of affected patients but could also be underestimated determining factors in the occurrence of IEMs. An epigenetic cause of IEMs has been recently described for the autosomal recessive methylmalonic aciduria and homocystinuria, cblC type (cblC disease), and it has been named epi-cblC. Epi-cblC has been reported in association with compound heterozygosity for a genetic variant and an epimutation at the MMACHC locus, which is secondary to a splicing variant (c.515-1G > T or c.515-2A > T) at the adjacent PRDX1 gene. Both these variants cause aberrant antisense transcription and cis-hypermethylation of the MMACHC gene promotor with subsequent silencing. Until now, only nine epi-cblC patients have been reported. METHODS: We report clinical/biochemical assessment, MMACHC/PRDX1 gene sequencing and genome-wide DNA methylation profiling in 11 cblC patients who had an inconclusive MMACHC gene testing. We also compare clinical phenotype of epi-cblC patients with that of canonical cblC patients. RESULTS: All patients turned out to have the epi-cblC disease. One patient had a bi-allelic MMACHC epimutation due to the homozygous PRDX1:c.515-1G > T variant transmitted by both parents. We found that the bi-allelic epimutation produces the complete silencing of MMACHC in the patient's fibroblasts. The remaining ten patients had a mono-allelic MMACHC epimutation, due to the heterozygous PRDX1:c.515-1G > T, in association with a mono-allelic MMACHC genetic variant. Epi-cblC disease has accounted for about 13% of cblC cases diagnosed by newborn screening in the Tuscany and Umbria regions since November 2001. Comparative analysis showed that clinical phenotype of epi-cblC patients is similar to that of canonical cblC patients. CONCLUSIONS: We provide evidence that epi-cblC is an underestimated cause of inborn errors of cobalamin metabolism and describe the first instance of epi-cblC due to a bi-allelic MMACHC epimutation. MMACHC epimutation/PRDX1 mutation analyses should be part of routine genetic testing for all patients presenting with a metabolic phenotype that combines methylmalonic aciduria and homocystinuria.

Multicentric Retrospective Evaluation of Five Classic Infantile Pompe Disease Subjects Under Enzyme Replacement Therapy With Early Infratentorial Involvement.

White matter (WM) abnormalities and ventricular enlargement in brain MRI are well-known features in infantile-onset Pompe disease (IOPD) in the era of enzyme replacement therapy (ERT). In this multicentric observational retrospective study, we report a small cohort of IOPD subjects under ERT treatment (n = 5, median age at MRI = 7.4 years, median period of treatment = 85 months) that showed the classic features of extensive supratentorial WM abnormalities but also unusual findings such as early infratentorial WM abnormalities and late supratentorial U-fiber involvement. Given the recent implementation of ERT and the rarity of the disease, a complete spectrum of presentation and understanding of progressive pathology in the brain of IOPD subjects in treatment remains underacknowledged. The availability of long-term follow-up of IOPD subjects under ERT treatment allows a better insight into the evolution of brain abnormalities in such disease.

Clinical problems and everyday abilities of a group of Italian adolescent and young adults with Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly/mental retardation syndrome, characterized by distinctive facial features, generalized hirsutism, growth and cognitive dysfunction, microcephaly and limb abnormalities. Currently mutations of three different genes, NIPBL, SMC1A, and SMC3, are known to be related to the CdLS phenotype with an overall detection rate of about 50%. Few data are available regarding the level of autonomy in everyday life of CdLS patients. Due to the collaboration of the Italian parents' support group, we collected information regarding clinical and behavioral problems and everyday abilities of 45 CdLS patients between 13 and 39 years, using a specific multi-item questionnaire. To better analyze clinical information we divided our patients into three groups according to age: 13-20, 21-29, and over 30 years. Data from clinical, malformative and behavioral problems were not significantly different from those described for CdLS patients. Regarding personal autonomies this study showed the significant limitations of these individuals. It is interesting to observe that patients between 21 and 29 years, showed the best performance, while those over 30 had more severe difficulties. We suggest that these data be interpreted as a minimum level of autonomy achievable for CdLS adolescent/young adults, as the level of care, rehabilitation and stimulation of these patients has increased in the last 30 years.

High-frequency rhythmic cortical myoclonus in a long-surviving patient with nonketotic hypergylcemia.

An 11-year-old girl with nonketotic hyperglycinemia who typically presented with a picture of early myoclonic encephalopathy in the neonatal period is presented in this article. Treated early with sodium benzoate and dextromethorphan, she became seizure-free, while myoclonus persisted. During examination, multifocal rhythmic myoclonic jerks in gamma frequency enhanced by motor activity were noted. Coherence analysis of the electroencephalography-electromyography relationship indicated a cortical origin of the myoclonic jerks. Observation of this case suggests that rhythmic cortical myoclonus may represent a late evolution of this rare disorder.