Characterization of central manifestations in patients with Niemann-Pick disease type C.

PURPOSE: Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease characterized by progressive neurodegeneration and neuropsychiatric symptoms. This study investigated pathophysiological mechanisms underlying motor deficits, particularly speech production, and cognitive impairment. METHODS: We prospectively phenotyped 8 adults with NPC and age-sex-matched healthy controls using a comprehensive assessment battery, encompassing clinical presentation, plasma biomarkers, hand-motor skills, speech production, cognitive tasks, and (micro-)structural and functional central nervous system properties through magnetic resonance imaging. RESULTS: Patients with NPC demonstrated deficits in fine-motor skills, speech production timing and coordination, and cognitive performance. Magnetic resonance imaging revealed reduced cortical thickness and volume in cerebellar subdivisions (lobule VI and crus I), cortical (frontal, temporal, and cingulate gyri) and subcortical (thalamus and basal ganglia) regions, and increased choroid plexus volumes in NPC. White matter fractional anisotropy was reduced in specific pathways (intracerebellar input and Purkinje tracts), whereas diffusion tensor imaging graph theory analysis identified altered structural connectivity. Patients with NPC exhibited altered activity in sensorimotor and cognitive processing hubs during resting-state and speech production. Canonical component analysis highlighted the role of cerebellar-cerebral circuitry in NPC and its integration with behavioral performance and disease severity. CONCLUSION: This deep phenotyping approach offers a comprehensive systems neuroscience understanding of NPC motor and cognitive impairments, identifying potential central nervous system biomarkers.

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.

A pilot investigation of muscle integrity in patients with ADSSL1 myopathy using electrical impedance myography.

INTRODUCTION/AIMS: ADSSL1 myopathy (OMIM 617030) is a recently discovered, congenital myopathic disease caused by a pathogenic variant in ADSSL1. ADSSL1 is an enzyme involved in the purine nucleotide process and facilitates the conversion of inosine monophosphate to adenosine monophosphate within myocytes. Electrical impedance myography (EIM) is a portable, non-invasive, and cost-effective method for characterizing muscle integrity. Three ADSSL1 patients are presented in whom characterization of muscle integrity using EIM was performed. METHODS: A 15-y-old male, 20-y-old female, and 63-y-old male each with a pathogenic variant in ADSSL1 [c.901G > A] as well as three, age-gender matched healthy controls (HCs) were enrolled. Study participants were phenotyped using a virtual EIM procedure. RESULTS: ADSSL1 myopathy patients presented with variable onset of physical disability, disease progression, and severity of muscle weakness. Across multiple proximal and distal muscles groups and relative to HCs, ADSSL1 myopathy patients demonstrated lower phase and reactance values, while resistance was higher, which together indicated diseased muscle. DISCUSSION: EIM can provide a novel, non-invasive and objective biomarker to evaluate muscle integrity in patients with ADSSL1 myopathy. Combining EIM with musculoskeletal imaging and histologic assessments in follow-up studies may further inform on the pathophysiology of ADSSL1 myopathy.

Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.

We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.

Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus.

Several guidelines are available for identification and management of patients with Gaucher disease, but the most recent guideline was published in 2013. Since then, there have been significant advances in newborn screening, phenotypic characterization, identification of biomarkers and their integration into clinical practice, and the development and approval of new treatment options. Accordingly, the goal of this Delphi consensus exercise was to extend prior initiatives of this type by addressing issues related to newborn screening, diagnostic evaluations, and treatment (both disease directed and adjunctive). The iterative Delphi process involved creation of an initial slate of statements, review by a steering committee, and three rounds of consensus development by an independent panel. A preliminary set of statements was developed by the supporting agency based on literature searches covering the period from 1965 to 2020. The Delphi process reduced an initial set of 185 statements to 65 for which there was unanimous support from the panel. The statements supported may ultimately provide a framework for more detailed treatment guidelines. In addition, the statements for which unanimous support could not be achieved help to identify evidence gaps that are targets for future research.

3-Hydroxyisobutyric acid dehydrogenase deficiency: Expanding the clinical spectrum and quantitation of D- and L-3-Hydroxyisobutyric acid by an LC-MS/MS method.

A deficiency of 3-hydroxyisobutyric acid dehydrogenase (HIBADH) has been recently identified as a cause of primary 3-hydroxyisobutyric aciduria in two siblings; the only previously recognized primary cause had been a deficiency of methylmalonic semialdehyde dehydrogenase, the enzyme that is immediately downstream of HIBADH in the valine catabolic pathway and is encoded by the ALDH6A1 gene. Here we report on three additional patients from two unrelated families who present with marked and persistent elevations of urine L-3-hydroxyisobutyric acid (L-3HIBA) and a range of clinical findings. Molecular genetic analyses revealed novel, homozygous variants in the HIBADH gene that are private within each family. Evidence for pathogenicity of the identified variants is presented, including enzymatic deficiency of HIBADH in patient fibroblasts. This report describes new variants in HIBADH as an underlying cause of primary 3-hydroxyisobutyric aciduria and expands the clinical spectrum of this recently identified inborn error of valine metabolism. Additionally, we describe a quantitative method for the measurement of D- and L-3HIBA in plasma and urine and present the results of a valine restriction therapy in one of the patients.

Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data.

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

Health Care for Mitochondrial Disorders in Canada: A Survey of Physicians.

BACKGROUND: An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care. METHODS: We conducted a cross-sectional survey of Canadian physicians involved in the diagnosis and/or ongoing care of patients with mitochondrial diseases. We used snowball sampling to identify potentially eligible participants, who were contacted by mail up to five times and invited to complete a questionnaire by mail or internet. The questionnaire addressed: personal experience in providing care for mitochondrial disorders; diagnostic and treatment practices; challenges in accessing tests or treatments; and views regarding research priorities. RESULTS: We received 58 survey responses (52% response rate). Most respondents (83%) reported spending 20% or less of their clinical practice time caring for patients with mitochondrial disorders. We identified important variation in diagnostic care, although assessments frequently reported as diagnostically helpful (e.g., brain magnetic resonance imaging, MRI/MR spectroscopy) were also recommended in published guidelines. Approximately half (49%) of participants would recommend "mitochondrial cocktails" for all or most patients, but we identified variation in responses regarding specific vitamins and cofactors. A majority of physicians recommended studies on the development of effective therapies as the top research priority. CONCLUSIONS: While Canadian physicians' views about diagnostic care and disease management are aligned with published recommendations, important variations in care reflect persistent areas of uncertainty and a need for empirical evidence to support and update standard protocols.

Les soins de santé prodigués au Canada à des individus atteints de troubles mitochondriaux : une enquête menée auprès de médecins. Contexte: Dans le cas de patients atteints de troubles mitochondriaux rares, il est permis de croire qu'une meilleure compréhension des pratiques en matière de diagnostic et de traitement peut contribuer, au moyen des lignes directrices, à l'étalonnage et à l'établissement de priorités en ce qui regarde la recherche évaluative. Notre intention a été de décrire les soins prodigués au Canada par des médecins, notamment leur variabilité, dans le cas de ces patients. Méthodes: Pour ce faire, nous avons effectué une enquête transversale auprès de médecins canadiens qui posent des diagnostics de troubles mitochondriaux et qui prodiguent des soins continus aux patients qui en sont atteints. À cet effet, nous avons fait appel à la méthode d'enquête dite « en boule de neige ¼ (snowball sampling) afin d'identifier des participants possiblement admissibles. Ces derniers ont été ensuite contactés par la poste, et ce, à cinq reprises au maximum. Ils ont été invités à remplir un questionnaire et à le retourner par la poste ou en ligne. Ce questionnaire abordait les aspects suivants : leur expérience personnelle à titre de prestataire de soins ; leurs pratiques en matière de diagnostic et de traitement ; les défis se présentant à eux au moment d'avoir accès à des tests ou à des traitements ; et finalement leurs points de vue en ce qui regarde les priorités de la recherche. Résultats: Dans le cadre de cette enquête, nous avons reçu 58 réponses, ce qui représente un taux de 52 %. Une majorité de répondants (83 %) ont indiqué allouer 20 % ou moins de leur temps de pratique clinique aux soins de patients atteints de ces troubles. Nous avons également noté d'importantes variations concernant les soins et les diagnostics, et ce, même si les outils d'évaluation fréquemment considérés utiles sur le plan diagnostic (p. ex. : des IRM du cerveau/la spectroscopie par RM) étaient également recommandés dans des lignes directrices déjà publiées. Environ la moitié de nos répondants (49 %) recommanderaient volontiers un « cocktail ¼ de vitamines pour tous leurs patients ou la plupart d'entre eux. Quand il est question de vitamines spécifiques et de cofacteurs, nous avons cependant identifié une variation dans leurs réponses. Interrogés quant à la priorité numéro un en matière de recherche, une majorité de répondants a dit recommander la poursuite d'études portant sur la mise sur pied de traitements thérapeutiques efficaces. Conclusions: Bien que les points de vue de ces médecins canadiens en ce qui regarde les diagnostics et la prise en charge des troubles mitochondriaux soient en phase avec des recommandations publiées, d'importantes variations reflètent la persistance d'aspects incertains ainsi qu'un besoin de données empiriques afin de renforcer et de mettre à jour les protocoles de rééférence.

Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency.

BACKGROUND: A high level of succinylacetone (SA) in blood is a sensitive, specific newborn screening marker for hepatorenal tyrosinemia type 1 (HT1, MIM 276700) caused by deficiency of fumarylacetoacetate hydrolase (FAH). Newborns with HT1 are usually clinically asymptomatic but show liver dysfunction with coagulation abnormalities (prolonged prothrombin time and/or high international normalised ratio). Early treatment with nitisinone (NTBC) plus dietary restriction of tyrosine and phenylalanine prevents the complications of severe liver disease and neurological crises. METHODS AND RESULTS: Six newborns referred for hypersuccinylacetonaemia but who had normal coagulation testing on initial evaluation had sequence variants in the GSTZ1 gene, encoding maleylacetoacetate isomerase (MAAI), the enzyme preceding FAH in tyrosine degradation. Initial plasma SA levels ranged from 233 to 1282 nmol/L, greater than normal (<24 nmol/L) but less than the initial values of patients with HT1 (16 944-74 377 nmol/L, n=15). Four individuals were homozygous for c.449C>T (p.Ala150Val). One was compound heterozygous for c.259C>T (p.Arg87Ter) and an intronic sequence variant. In one, a single heterozygous GSTZ1 sequence variant was identified, c.295G>A (p.Val99Met). Bacterial expression of p.Ala150Val and p.Val99Met revealed low MAAI activity. The six individuals with mild hypersuccinylacetonaemia (MHSA) were not treated with diet or nitisinone. Their clinical course has been normal for up to 13 years. CONCLUSIONS: MHSA can be caused by sequence variants in GSTZ1. Such individuals have thus far remained asymptomatic despite receiving no specific treatment.

A checklist for managed access programmes for reimbursement co-designed by Canadian patients and caregivers.

INTRODUCTION: Reimbursement decisions on orphan drugs carry significant uncertainty, and as the amount increases, so does the risk of making a wrong decision, where harms outweigh benefits. Consequently, patients often face limited access to orphan drugs. Managed access programmes (MAPs) are a mechanism for managing risk while enabling access to potentially beneficial drugs. Patients and their caregivers have expressed support for these programmes and see patient input as critical to successful implementation. However, they have yet to be systematically involved in their design. OBJECTIVE: The aim of this study was to co-design with patients and caregivers a tool for the development of managed access programmes. METHODS: Building upon established relationships with the Canadian Organization for Rare Disorders, the project team collaborated with patients and caregivers using the principles of participatory action research. Data were collected at two workshops and analysed using a thematic network approach. RESULTS: Patients and caregivers co-designed a checklist comprised of six aspects of an ideal MAP relating to accountability (programme goals); governance (MAP-specific committee oversight, patient input, international collaboration); and evidence collection (outcome measures and continuation criteria, on-going monitoring and registries). They recognized that health-care resources are finite and considered disease or drug eligibility criteria for deciding when to use a MAP (eg drugs treating diseases for which there are no other legitimate alternatives). CONCLUSIONS: A patient and caregiver-designed checklist was created, which emphasized patient involvement and transparency. Further research is needed to examine the feasibility of this checklist and roles for other stakeholders.

Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome.

Pyridoxine-dependent epilepsy (PDE) is an epileptic encephalopathy characterized by response to pharmacologic doses of pyridoxine. PDE is caused by deficiency of α-aminoadipic semialdehyde dehydrogenase resulting in impaired lysine degradation and subsequent accumulation of α-aminoadipic semialdehyde. Despite adequate seizure control with pyridoxine monotherapy, 75% of individuals with PDE have significant developmental delay and intellectual disability. We describe a new combined therapeutic approach to reduce putative toxic metabolites from impaired lysine metabolism. This approach utilizes pyridoxine, a lysine-restricted diet to limit the substrate that leads to neurotoxic metabolite accumulation and L-arginine to compete for brain lysine influx and liver mitochondrial import. We report the developmental and biochemical outcome of six subjects who were treated with this triple therapy. Triple therapy reduced CSF, plasma, and urine biomarkers associated with neurotoxicity in PDE. The addition of arginine supplementation to children already treated with dietary lysine restriction and pyridoxine further reduced toxic metabolites, and in some subjects appeared to improve neurodevelopmental outcome. Dietary lysine restriction was associated with improved seizure control in one subject, and the addition of arginine supplementation increased the objective motor outcome scale in two twin siblings, illustrating the contribution of each component of this treatment combination. Optimal results were noted in the individual treated with triple therapy early in the course of the disease. Residual disease symptoms could be related to early injury suggested by initial MR imaging prior to initiation of treatment or from severe epilepsy prior to diagnosis. This observational study reports the use of triple therapy, which combines three effective components in this rare condition, and suggests that early diagnosis and treatment with this new triple therapy may ameliorate the cognitive impairment in PDE.

The experience of living with Niemann-Pick type C: a patient and caregiver perspective.

BACKGROUND: Niemann-Pick disease type C (NPC) is a rare inherited lysosomal storage disease typified by accumulation of cholesterol and other lipids in late endosomes/lysosomes, thereby resulting in a spectrum of neurological, psychiatric, and systemic symptoms (notably liver disease). Though it is well-known that NPC exacts a physical and emotional toll on both patients and caregivers, the burden of NPC can vary between patients, while the challenges of living with NPC can evolve over time (i.e., from time of diagnosis to the present day). To further grasp patient and caregiver perceptions and experiences with NPC, we carried out focus group discussions with pediatric and adult individuals with NPC (N = 19), with partial or full representation of the patient by their caregiver. Furthermore, we utilized our NPC focus group discussion to provide guidance on study design parameters and feasibility of prospective investigations aiming to characterize the central manifestations of NPC using neuroimaging, specifically, magnetic resonance imaging (MRI) methodology. RESULTS: Focus group discussions revealed that neurological signs, including declining cognition, memory loss, and psychiatric symptoms, as well as increasingly impaired mobility and motor function, are among the most pressing past and current concerns for patients and caregivers. Moreover, several participants also expressed concern over a loss of independence, social exclusion, and uncertainty for what the future holds. Caregivers described the challenges that participation in research poses, which included logistical difficulties mainly due to traveling with medical equipment and the need for sedation in a minority of patients when undergoing MRI. CONCLUSIONS: The findings derived from focus group discussions highlight the outstanding challenges that NPC patients and their caregivers face daily, while also providing direction on the potential scope and feasibility of future studies focusing on the central phenotypes of NPC.

Case report: Chronic pain in a pediatric patient with late-onset pompe disease.

Pompe disease (PD) is a rare inherited metabolic disorder of deficient or absent acid alpha-glucosidase (GAA), resulting in defective lysosomal glycogen catabolism. Muscle weakness, respiratory deficiency and gastrointestinal symptoms are commonly monitored in PD. However, pain and associated psychological symptoms are less focused upon. A pediatric patient with late-onset Pompe disease (LOPD) comorbid with chronic pain is presented. Symptoms of pain in the feet were first reported between 6 and 7 years of age and were attributed to growing pains. Following progression of lower body pain, weakness, fatigue, and difficulties with ambulation, a thorough clinical assessment including genetic testing was performed, which led to a diagnosis of LOPD at 9 years of age. ERT with recombinant human alglucosidase alfa was subsequently started. The patient's clinical status is compounded by depressed mood, anxiety, and attention deficit hyperactivity disorder, which may further exacerbate pain. A multidisciplinary pain treatment approach consisting of orthopedics, physical therapy, and psychosocial therapy aimed at enhancing pain coping skills is described for this LOPD patient. This case highlights the need for a greater understanding of pain generation and identification of optimized pain treatment approaches in children with LOPD that can be implemented alongside ERT.

Novel clinical findings in a case of postnatally diagnosed trisomy 12 mosaicism.

We report on a girl with trisomy 12 mosaicism diagnosed postnatally. She has been followed from 4 months of age for developmental delay, unilateral sensorineural hearing loss, intestinal malrotation, hemi-hyperplasia, pigmentary dysplasia, retinopathy, and a vascular ring. To our knowledge, there have been no reports of complete trisomy 12 in the literature. However there have been a few reports describing the phenotype of individuals with trisomy 12 mosaicism. This case report is a description of the eighth liveborn individual diagnosed postnatally with this condition.

Targeting neurological abnormalities in lysosomal storage diseases.

Central nervous system (CNS) abnormalities and corresponding neurological and psychiatric symptoms are frequently observed in lysosomal storage disorders (LSDs). The genetic background of individual LSDs is indeed unique to each illness. However, resulting defective lysosomal function within the CNS can transition normal cellular processes (i.e., autophagy) into aberrant mechanisms, facilitating overlapping downstream consequences including neurocircuitry dysfunction, neurodegeneration as well as sensory, motor, cognitive, and psychological symptoms. Here, the neurological and biobehavioral phenotypes of major classes of LSDs are discussed alongside therapeutic strategies in development that aim to tackle neuropathology among other disease elements. Finally, focused ultrasound blood-brain barrier opening is proposed to enhance therapeutic delivery thereby overcoming the key hurdle of central distribution of disease modifying therapies in LSDs.

Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels.

BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. AIM: We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate. METHODS: Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS). RESULTS: Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable. CONCLUSION: KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.

Family Experiences with Care for Children with Inherited Metabolic Diseases in Canada: A Cross-Sectional Survey.

BACKGROUND AND OBJECTIVE: Children with inherited metabolic diseases often require complex and highly specialized care. Patient and family-centered care can improve health outcomes that are important to families. This study aimed to examine experiences of family caregivers (parents/guardians) of children diagnosed with inherited metabolic diseases with healthcare to inform strategies to improve those experiences. METHODS: A cross-sectional mailed survey was conducted of family caregivers recruited from an ongoing cohort study. Participants rated their healthcare experiences during their child's visits to five types of healthcare settings common for inherited metabolic diseases: the metabolic clinic, the emergency department, hospital inpatient units, the blood laboratory, and the pharmacy. Participants provided narrative descriptions of any memorable negative or positive experiences. RESULTS: There were 248 respondents (response rate 49%). Caregivers were generally very or somewhat satisfied with the care provided at each care setting. Appropriate treatment, provider knowledge, provider communication, and care coordination were deemed essential aspects of satisfaction with care by the majority of participants across many settings. Memorable negative experiences were reported by 8-22% of participants, varying by setting. Among participants who reported memorable negative experiences, contributing factors included providers' demeanor, lack of communication, lack of involvement of the family, and disregard of an emergency protocol letter provided by the family. CONCLUSIONS: While caregivers' satisfaction with care for children with inherited metabolic diseases was high, we identified gaps in family-centered care and factors contributing to negative experiences that are important to consider in the future development of strategies to improve pediatric care for inherited metabolic diseases.

Discordant phenotypes in a mother and daughter with mosaic supernumerary ring chromosome 19 explained by a de novo 7q36.2 deletion and 7p22.1 duplication.

We report on a patient with severe intellectual disability, microcephaly, short stature, and dysmorphic features who, based on standard karyotyping, has two cytogenetic abnormalities: an apparently balanced paracentric inversion of chromosome 7, inv(7)(q31.2q36), and a small supernumerary ring chromosome derived entirely of material from chromosome 19. While the inversion was detected in all cells, mosaicism was observed for the ring chromosome. Interestingly, apparently identical cytogenetic abnormalities were detected in the patient's mother, who presented with normal stature, few dysmorphic features, and normal cognition without microcephaly. While the level of mosaicism could not adequately explain the phenotypic discordance, comparative genome hybridization revealed a de novo terminal deletion of chromosome 7, del(7)(q36.2), and a terminal duplication of chromosome 7, dup(7)(p22.1) in the patient. Additional cytogenetic investigation revealed that the patient inherited a recombinant chromosome derived from a cryptic maternal pericentric inversion: inv(7)(p22q36). The patient's distinctive features are consistent with the wide phenotypic spectrum reported in 7p duplication and 7q terminal deletion syndromes. These chromosomal regions contain several candidate genes of clinical significance, including SHH, EN2, and FAM20C. Our findings strongly suggest that our patient's phenotype is largely attributable to partial 7pter trisomy and partial 7qter monosomy rather than mosaic supernumerary ring chromosome 19.

PURA-Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum.

BACKGROUND AND OBJECTIVES: Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients. METHODS: Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. RESULTS: A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations. DISCUSSION: The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.