Clinical characteristics of children with Borrelia-related peripheral facial palsy and utility of cerebrospinal fluid testing.

AIM: To describe the aetiology and clinical characteristics of acute peripheral facial palsy (PFP) in children and investigate the utility of the European Federation of Neurological Societies (EFNS) criteria for diagnosing Borrelia-related PFP (BPFP) based on cerebrospinal fluid (CSF) testing and the Centers for Disease Control and Prevention (CDC) criteria based on serology. METHODS: We retrospectively identified children aged <18 years diagnosed with acute PFP between 2014 and 2020. We used the EFNS criteria as the gold standard and the CDC criteria for diagnosing BPFP. RESULTS: Out of 257 children with PFP, 93 (36%) fulfilled the EFNS or CDC criteria for BPFP. We found a discrepancy between the EFNS criteria with CSF testing and the CDC without CSF testing in 27 (14%) of the 190 children with available data. Of the 37 children with PFP and ≥2 symptoms of fever, fatigue, nausea/vomiting or meningeal symptoms, 31 (84%) fulfilled the EFNS criteria for BPFP. CONCLUSION: Borrelia is a common cause of PFF in children, and its prevalence is higher in children with systemic symptoms. Also, CSF testing did not have decisive management implications in most cases. Therefore, clinical evaluation and Borrelia serology could be the initial steps in the diagnosis of PFP in children.

Manifestations of X-linked pyruvate dehydrogenase complex deficiency in female PDHA1 carriers.

BACKGROUND AND PURPOSE: Pyruvate dehydrogenase complex deficiency is in up to 90% caused by pathogenic variants in the X-linked PDHA1 gene. We aimed to investigate female relatives of index patients with PDHA1-related disease to (i) describe the prevalence of female PDHA1 carriers, (ii) determine whether they had symptoms and signs, and (iii) delineate the associated phenotype. METHODS: In a national population-based study, we identified 37 patients with pathogenic variants in PDHA1. Sanger sequencing for the presence of the pathogenic variant was performed in their mothers and female relatives. The identified female carriers were clinically assessed, and their medical records were reviewed. RESULTS: The proportion carrying a de novo variant was 86%. We identified seven female PDHA1 carriers from five families. Five of them exhibited clinical features of the disease and were previously undiagnosed; all had signs of peripheral axonal neuropathy, four presented with strokelike episodes including two with Leigh-like lesions, and three had facial stigmata. CONCLUSIONS: PDHA1-related disease is underrecognized in heterozygous female carriers. Peripheral axonal neuropathy, strokelike and Leigh-like changes, and facial dysmorphism should raise suspicion of the disorder. Genetic analysis and clinical examination of potential female carriers are important for genetic counseling and have implications for treatment.

Correlation of mitochondrial respiration in platelets, peripheral blood mononuclear cells and muscle fibers.

There is a growing interest for the possibility of using peripheral blood cells (including platelets) as markers for mitochondrial function in less accessible tissues. Only a few studies have examined the correlation between respiration in blood and muscle tissue, with small sample sizes and conflicting results. This study investigated the correlation of mitochondrial respiration within and across tissues. Additional analyses were performed to elucidate which blood cell type would be most useful for assessing systemic mitochondrial function. There was a significant but weak within tissue correlation between platelets and peripheral blood mononuclear cells (PBMCs). Neither PBMCs nor platelet respiration correlated significantly with muscle respiration. Muscle fibers from a group of athletes had higher mass-specific respiration, due to higher mitochondrial content than non-athlete controls, but this finding was not replicated in either of the blood cell types. In a group of patients with primary mitochondrial diseases, there were significant differences in blood cell respiration compared to healthy controls, particularly in platelets. Platelet respiration generally correlated better with the citrate synthase activity of each sample, in comparison to PBMCs. In conclusion, this study does not support the theory that blood cells can be used as accurate biomarkers to detect minor alterations in muscle respiration. However, in some instances, pronounced mitochondrial abnormalities might be reflected across tissues and detectable in blood cells, with more promising findings for platelets than PBMCs.

Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries.

BACKGROUND: For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care. METHODS: A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics. RESULTS: Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1-3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1-5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries. CONCLUSION: HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians' struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.

Overuse of EEG and ECG in children with breath-holding spells and its implication for the management of the spells.

AIM: Breath-holding spells (BHS) are common in children, but evidence-based clinical guidelines are lacking. We investigated a large population-based cohort of BHS patients, to propose a refined description of typical BHS and guidelines for its management. METHODS: In a cross-sectional retrospective study, patients diagnosed with BHS in Southern Sweden 2004-2018 were recruited. Disease characteristics and diagnostic data were collected from patient medical records. RESULTS: In total, 519 patients, mean age at diagnosis 19.8 ± 13.8 months with equal gender distribution, were included. In 48.3%, BHS had already been diagnosed after one spell. During spells, 78.0% of patients were unresponsive. For 71.5%, atonic, tonic, tonic-clonic or myoclonic seizures were reported, and 78.0% of patients had a spell lasting less than 1 min. Electroencephalography was conducted in 30.4% and Electrocardiography in 45.1%. Six children (3.8%) had a pathological electroencephalogram, four of which had concomitant epilepsy and only 0.9% of children had electrocardiogram findings suggesting pathology, none showing long QT syndrome. CONCLUSION: Children with BHS were frequently subjected to unnecessary diagnostic interventions. We characterise a typical presentation of BHS and propose a management-algorithm, which is expected to reduce unnecessary usage of electroencephalography and electrocardiography.

The evolution of epilepsy surgery in tuberous sclerosis in Sweden: A national registry study.

PURPOSE: This study aimed to characterize the Swedish cohort of surgically treated patients with TSC and explore differences in preoperative investigation and outcome over time. METHODS: Data on patient and seizure characteristics were retrieved from the Swedish National Epilepsy Surgery Register. Two-year follow-up results were compared between the years 1997-2010 and 2011-2018. Preoperative investigations were re-evaluated. RESULTS: Eighteen tuberectomies and seven callosotomies were identified. Seizure freedom after tuberectomy was achieved in 11 % (1/9) 1997-2010 and 56 % (5/9) 2011-2018. The number of tuberectomies increased each decade. Patients operated on in 1997-2010 had higher seizure frequency (median 175 seizures/month vs. 102) and incidence of infantile spasms (4/9 vs. 1/9, none after 2011). There was a trend towards surgery at a younger age (median 86 months 1997-2010 vs. 48 months 2011-2018). None with >200 seizure/month, SEGA, or history of infantile spasms achieved seizure freedom. Two patients underwent anterior callosotomy (1992 and 1994) and became free of drop attacks. Five callosotomies were performed between 2011 and 2013, one patient became free of drop attacks. Two complications with new neurological deficits were reported. The median age at surgery was higher in the callosotomy group (14 years) than in the tuberectomy group (5 years). CONCLUSION: Seizure freedom after tuberectomy in patients with TSC has increased over time in our cohort. Signs of a heavier disease burden were more frequently observed 1997-2010 and associated with worse outcomes. Callosotomy operations were prevalent at the beginning of the 2010s.

Childhood tuberous sclerosis complex in southern Sweden: a paradigm shift in diagnosis and treatment.

AIM: To investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time. METHODS: In this retrospective observational study, 52 individuals aged up to 18 years at the study start were followed-up at regional hospitals and centres for habilitation from 2000 to 2020. RESULTS: Cardiac rhabdomyoma was detected prenatally/neonatally in 69.2% of the subjects born during the latest ten years of the study period. Epilepsy was diagnosed in 82.7% of subjects, and 10 (19%) were treated with everolimus, mainly (80%) for a neurological indication. Renal cysts were detected in 53%, angiomyolipomas in 47%, astrocytic hamartomas in 28% of the individuals. There was a paucity of standardized follow-up of cardiac, renal, and ophthalmological manifestations and no structured transition to adult care. CONCLUSION: Our in-depth analysis shows a clear shift towards an earlier diagnosis of tuberous sclerosis complex in the latter part of the study period, where more than 60% of cases showed evidence of this condition already in utero due to the presence of a cardiac rhabdomyoma. This allows for preventive treatment of epilepsy with vigabatrin and early intervention with everolimus for potential mitigation of other symptoms of tuberous sclerosis complex.

Thrombosis risk with estrogen use for puberty induction in congenital disorders of glycosylation.

Congenital disorders of glycosylation are a group of rare related disorders causing multisystem dysfunction, including ovarian failure in females that requires early estrogen replacement. Glycosylation defects also disrupt normal synthesis of several coagulation factors, increasing thrombotic risks and complicating hormone replacement. This series describes four females with different types of CDG who developed venous thromboses while on transdermal estrogen replacement. The authors highlight the knowledge gaps around anticoagulation for this population and propose further investigations.

The Swedish COG6-CDG experience and a comprehensive literature review.

Here, we present the first two Swedish cases of Conserved Oligomeric Golgi complex subunit 6-congenital disorders of glycosylation (COG6-CDG). Their clinical symptoms include intellectual disability, Attention Deficit/Hyperactivity Disorder (ADHD), delayed brain myelinization, progressive microcephaly, joint laxity, hyperkeratosis, frequent infections, and enamel hypoplasia. In one family, compound heterozygous variants in COG6 were identified, where one (c.785A>G; p.Tyr262Cys) has previously been described in patients of Moroccan descent, whereas the other (c.238G>A; p.Glu80Lys) is undescribed. On the other hand, a previously undescribed homozygous duplication (c.1793_1795dup) was deemed the cause of the disease. To confirm the pathogenicity of the variants, we treated patient and control fibroblasts with the ER-Golgi transport inhibitor Brefeldin-A and show that patient cells manifest a significantly slower anterograde and retrograde ER-Golgi transport.

Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.

PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

A Retrospective Evaluation of the Predictive Value of Newborn Screening for Vitamin B12 Deficiency in Symptomatic Infants Below 1 Year of Age.

BACKGROUND: The sensitivity of newborn screening (NBS) in detecting infants that later develop symptomatic vitamin B12 deficiency is unknown. We evaluated the predictive value using NBS algorithms in detecting infants that later were clinically diagnosed with symptomatic B12 deficiency. Furthermore, we investigated whether being born in a hospital using nitrous oxide (N2O) as pain relief in labor may have had an impact on total homocysteine at NBS. METHODS: We retrospectively retrieved NBS data and analyzed total homocysteine, methylmalonic acid and methyl citrate on stored NBS dried blood spots (DBS) of 70 infants diagnosed with symptomatic B12 deficiency and compared them to 646 matched and 434 unmatched DBS controls to evaluate the Austrian and Heidelberg B12 NBS algorithms. RESULTS: The sensitivity of NBS in detecting infants later diagnosed with symptomatic B12 deficiency at median age 10.9 weeks was ≤10%. Total homocysteine was higher in DBS for the unmatched controls who were born in hospitals providing N2O compared to in hospitals not providing N2O, with median total homocysteine 4.0 µmol/L compared to 3.5 µmol/L (n = 434, 95% CI 0.04-0.87, p = 0.03). CONCLUSION: NBS algorithms were unable to identify most infants diagnosed with symptomatic B12 deficiency after the neonatal period. Being born in hospitals providing N2O may impact total homocysteine at NBS.

Satisfaction and seizure outcomes of epilepsy surgery in tuberous sclerosis: A Swedish population-based long-term follow-up study.

PURPOSE: We conducted a cross-sectional study to evaluate long-term outcomes of epilepsy surgery in tuberous sclerosis complex (TSC) in a Swedish population. METHODS: Demographic and seizure data was retrieved from the Swedish National Epilepsy Surgery Registry and medical records. Patient reported outcome measurements (PROM) were determined by telephonic interviews at long term follow-up. RESULTS: Median follow-up was 6 y 8 m (range, 3-15 y 1 m) for tuberectomies (n = 15) and 3 y 6 m (range 2-10 y) for callosotomies (n = 7). Eight of the 15 tuberectomy participants were seizure-free. Four out of seven callosotomies were free from drop attacks. PROMs were provided by caregivers of 18/20 participants (data missing for two callosotomies). In the tuberectomy group, 6/8 patients were seizure-free and 3/7 had continued seizures; surgery was considered satisfactory and beneficial. Overall, satisfaction was high, even among patients who did not achieve remission; 13/15 tuberectomy responders recommended surgery to others with TSC and refractory epilepsy. None of the patients considered the surgery harmful. In the callosotomy group, satisfaction was low and congruent with the seizure outcome. All patients with continued drop attacks were unsatisfied; one considered surgery to be harmful. One participant, who would not recommend surgery to others, still perceived the surgery to be beneficial. CONCLUSIONS: This study confirmed that both tuberectomy and callosotomy are effective treatment options for TSC. Factors other than seizure outcomes seemed to have a major influence on satisfaction and perception of the benefit of surgery.

Nitrous oxide in labour predicted newborn screening total homocysteine and is a potential risk factor for infant vitamin B12 deficiency.

AIM: Risk factors for vitamin B12 deficiency in infants are not fully understood. The aim of the study was to assess predictors of total homocysteine and methylmalonic acid analysed in newborn screening dried blood spots. METHODS: In a Norwegian case control study, we analysed total homocysteine and methylmalonic acid in newborn screening dried blood spots of 86 infants clinically diagnosed with vitamin B12 deficiency during 2012-2018. Results were compared to 252 healthy infants and 400 dried blood spot controls. Medical records were reviewed, and mothers completed questionnaires. RESULTS: Both total homocysteine and methylmalonic acid were significantly higher on newborn screening dried blood spots in infants later clinically diagnosed with vitamin B12 deficiency than controls. Multiple regression analysis showed that the dose of nitrous oxide during labour was the strongest predictor for total homocysteine level in newborn screening dried blood spots for all infants, with larger effect in infants later clinically diagnosed with vitamin B12 deficiency than controls. CONCLUSION: Nitrous oxide dose during labour was a predictor for total homocysteine and may impact the interpretation of total homocysteine analysis in newborn screening. Nitrous oxide is suggested as a contributing risk factor for infants prone to develop vitamin B12 deficiency.

Paediatric emergency departments should manage young febrile and afebrile infants the same if they have a fever before presenting.

AIM: Our aim was to evaluate the risk of bacterial meningitis, bacteremia, and urinary tract infection (UTI) in infants ≤60 days who presented to paediatric emergency departments (PEDs) after having fever at home. We also investigated any differences between infants who were afebrile or febrile on presentation. METHODS: This was a multicenter retrospective study of infants ≤60 days presented to four Swedish PEDs during 2014-2020 with reported fever at home. We used relative risks (RR) to compare the prevalence of UTI, bacteremia, and bacterial meningitis between the infants who were afebrile and the infants who were still febrile when they presented to the PED. RESULTS: The cohort comprised 1926 infants, and 702 (36%) were afebrile on presentation. The prevalence of UTI in the afebrile and febrile infants was 6.1% [95% confidence interval (CI) 4.5-8.2] versus 14.2% (95% CI 12.3-16.2), corresponding to an RR of 0.43 (95% CI 0.31-0.59). In infants ≤28 days, the RR for meningitis was 1.05 (95% CI 0.18-6.23) for afebrile versus febrile infants. Five times more febrile infants underwent a lumbar puncture. CONCLUSION: Infants who were afebrile on presentation underwent fewer lumbar punctures, but they had similar rates of bacterial meningitis to febrile infants. Different management approaches are not justified.

Breastfed Infants With Spells, Tremor, or Irritability: Rule Out Vitamin B12 Deficiency.

BACKGROUND: In Norway, 5-10% of neonates and infants have biomarkers suggesting vitamin B12 deficiency from newborn screening tests and unselected clinical screening, respectively. AIMS: The aims were to identify risk factors and describe presenting symptoms and biochemical profiles in infants diagnosed with vitamin B12 deficiency. METHODS: In this case-control study, we searched hospital medical records for infants younger than one year born in 2011-2018, diagnosed with vitamin B12 deficiency. We compared 85 cases with a control group of 252 infants aged 3-7 months. Parents completed questionnaires. RESULTS: Of the 85 cases with vitamin B12 deficiency, 80% presented with spells (37%) of apneas, motor seizures, or absences within the first two months of life. Tremor (29%) and irritability (18%) were the most common findings at the first examination. Serum total homocysteine ≥10 µmol/L was found in 77% of cases compared to 28% of controls (P < 0.001). None of the mothers were vegetarians, but 25% reported a previous history of vitamin B12 deficiency and 7% had celiac disease. The dose of nitrous oxide given during labor was significantly associated with infant serum total homocysteine level at diagnosis (r = 0.37, 95% confidence interval = 0.16-0.55, P < 0.001) for cases, but not for controls. CONCLUSION: Spells, tremor, and irritability are common findings in early infant vitamin B12 deficiency. Nitrous oxide given during labor is proposed as a contributing risk factor to the development of early infant vitamin B12 deficiency.

Management and Outcome of Febrile Infants ≤60 days, With Emphasis on Infants ≤21 Days Old, in Swedish Pediatric Emergency Departments.

BACKGROUND: Management of febrile infants ≤60 days of age varies, and the age for routine investigations and antibiotic-treatment is debated. The American Academy of Pediatrics recommended age threshold for lumbar puncture (LP) is 21 days and for blood culture 60 days. We describe management and adverse outcome of febrile infants ≤60 days old, in Sweden. METHODS: Retrospective cross-sectional study of infants ≤60 days of age with fever without source evaluated in 4 University pediatric emergency departments, between 2014 and 2017. Adverse outcome was defined as delayed-treated invasive bacterial infection (IBI: meningitis or bacteremia). RESULTS: We included 1701 infants. In infants ≤21 days old, LP was performed in 16% (95% CI: 12-20) and blood culture in 43% (95% CI: 38-48). Meningitis was diagnosed in 5 (1.3%; 95% CI: 0.4-3.0) and bacteremia in 12 (4.5%; 95% CI: 2.6-7.0) infants. Broad-spectrum antibiotics were not administered to 66% (95% CI: 61-71), of which 2 (0.8%; 95% CI: 0.1-2.8) diagnosed with IBI (1 meningitis and 1 bacteremia). In the 29-60 days age group, blood culture was performed in 21% (95% CI: 19-24), and broad-spectrum antibiotics were not administered to 84% (95% CI: 82-86), with no case of delayed-treated bacteremia. CONCLUSIONS: The rates of LP, blood culture and broad-spectrum antibiotics were low. Despite that, there were few delayed-treated IBIs, but 2 of the 17 infants ≤21 days of age with IBI were not timely treated, which prompts the need for a safer approach for this age group. Also, the utility of routine blood culture for all febrile infants 29-60 days old could be questioned.

Novel imaging findings in pyruvate dehydrogenase complex (PDHc) deficiency-Results from a nationwide population-based study.

The vast clinical and radiological spectrum of pyruvate dehydrogenase complex (PDHc) deficiency continues to pose challenges both in diagnostics and disease monitoring. Prompt diagnosis is important to enable early initiation of ketogenic diet. The patients were recruited from an ongoing population-based study in Sweden. All patients with a genetically confirmed diagnosis who had been investigated with an MRI of the brain were included. Repeated investigations were assessed to study the evolution of the MRI changes. Sixty-two MRI investigations had been performed in 34 patients (23 females). The genetic cause was mutations in PDHA1 in 29, PDHX and DLAT in 2 each, and PDHB in 1. The lesions were prenatal developmental in 16, prenatal clastic in 18, and postnatal clastic in 15 individuals. Leigh-like lesions with predominant involvement of globus pallidus were present in 12, while leukoencephalopathy was present in 6 and stroke-like lesions in 3 individuals. A combination of prenatal developmental and clastic lesions was present in 15 individuals. In addition, one male with PDHA1 also had postnatal clastic lesions. The most common lesions found in our study were agenesis or hypoplasia of corpus callosum, ventriculomegaly, or Leigh-like lesions. Furthermore, we describe a broad spectrum of other MRI changes that include leukoencephalopathy and stroke-like lesions. We argue that a novel important clue, suggesting the possibility of PDHc deficiency on MRI scans, is the simultaneous presence of multiple lesions on MRI that have occurred during different phases of brain development.

De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus.

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.

The prevalence and clinical relevance of hyperhomocysteinemia suggesting vitamin B12 deficiency in presumed healthy infants.

BACKGROUND: Previous studies have demonstrated a high prevalence of biochemical vitamin B12 deficiency in infants in Norway. Increased total homocysteine (tHcy) is the most important marker of B12 deficiency in infants. There is a need to evaluate its clinical relevance. AIMS: To investigate the prevalence of hyperhomocysteinemia (S-tHcy > 8 µmol/L) suggestive of suboptimal B12 status and the prevalence of clinically relevant hyperhomocysteinemia in presumed healthy infants in Norway. Further, to evaluate risk factors, presence of symptoms and psychomotor development in these children. METHODS: In a prospective study we clinically examined 252 infants aged 3-7 months using standardized neurological and psychomotor tests prior to analyzing biochemical B12 deficiency markers in 250 infants. RESULTS: Twenty-five of 250 (10%) infants had hyperhomocysteinemia combined with clinically relevant symptoms suggestive of B12 deficiency. Hyperhomocysteinemia was associated with tremor, excessive sleep, and sub-normal scores in the fine motor section of the Ages and Stages Questionnaire. One-hundred and fourteen of 250 (46%) infants had hyperhomocysteinemia. Multiple regression analysis showed months of infant formula use as the strongest negative predictor for hyperhomocysteinemia. CONCLUSION: We have demonstrated associations between symptoms suggestive of infant B12 deficiency and increased levels of tHcy in presumed healthy infants The combination of hyperhomocysteinemia and associated relevant symptoms suggestive of B12 deficiency was a common finding, albeit most infants with hyperhomocysteinemia did not show symptoms.