James D. Weisfeld-Adams

Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

BackgroundRemethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions.ObjectiveTo summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management.Data sourcesReview, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach.Key recommendationsWe strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.

Ocular disease in the cobalamin C defect: A review of the literature and a suggested framework for clinical surveillance

The association between combined methylmalonic acidemia and homocystinuria of cblC type (cobalamin C defect, cblC) and ocular disease is now well recognized, and is a significant component of morbidity and disability associated with the condition. In this review, through collation of historically reported cases of early- and late-onset cblC and previously unreported cases, we have attempted to characterize the epidemiology, clinical features, and pathomechanisms of individual ocular features of cblC. These data suggest that maculopathy and nystagmus with abnormal vision are extremely common and affect the majority of children with early-onset cblC, usually before school age; strabismus and optic atrophy are also seen at relatively high frequency. The timing of progression of macular disease may coincide with a critical period of postnatal foveal development. Maculopathy and retinal disease may be subclinical and show only partial correlation with the extent of visual deficits, and visual deterioration may be relentlessly progressive in spite of aggressive treatment of biochemical abnormalities. In later-onset forms of the disease, visual loss and ocular complications appear to be infrequent. Finally, we discuss investigational strategies in diagnosing and characterizing eye disease in individuals with cblC, explore possible therapeutic avenues that may attenuate progression and severity of eye disease, and propose a clinical surveillance guideline for monitoring progression of ocular disease in children and adults with cblC.

De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis

OBJECTIVES To determine the incidence of pathogenic SCN8A variants in a cohort of epilepsy patients referred for clinical genetic testing. We also investigated the contribution of SCN8A to autism spectrum disorder, intellectual disability, and neuromuscular disorders in individuals referred for clinical genetic testing at the same testing laboratory. METHODS Sequence data from 275 epilepsy panels screened by Emory Genetics Laboratory were reviewed for variants in SCN8A. Two additional cases with variants in SCN8A were ascertained from other testing laboratories. Parental samples were tested for variant segregation and clinical histories were examined. SCN8A variants detected from gene panel analyses for autism spectrum disorder, intellectual disability, and neuromuscular disorders were also examined. RESULTS Five variants in SCN8A were identified in five individuals with epilepsy. Three variants were de novo, one was inherited from an affected parent, and one was inherited from an unaffected parent. Four of the individuals have epilepsy and developmental delay/intellectual disability. The remaining individual has a milder epilepsy presentation without cognitive impairment. We also identified an amino acid substitution at an evolutionarily conserved SCN8A residue in a patient who was screened on the autism spectrum disorder panel. Additionally, we examined the distribution of pathogenic SCN8A variants across the Nav1.6 channel and identified four distinct clusters of variants. These clusters are primarily located in regions of the channel that are important for the kinetics of channel inactivation. CONCLUSIONS Variants in SCN8A may be responsible for a spectrum of epilepsies as well as other neurodevelopmental disorders without seizures. The predominant pathogenic mechanism appears to involve disruption of channel inactivation, leading to gain-of-function effects.

Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6

Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m.8993T>G in high heteroplasmy or homoplasmy. Most patients were ascertained on newborn screening; most had normal enzymatic or molecular genetic testing to exclude biotinidase and holocarboxylase synthetase deficiencies. MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up. These cases expand the biochemical phenotype associated with MT-ATP6 mutations, especially m.8993T>G, to include acylcarnitine abnormalities mimicking carboxylase deficiency states. Clinicians should be aware of this association and its implications for newborn screening, and consider mtDNA sequencing in patients exhibiting similar acylcarnitine abnormalities that are biotin-unresponsive and in whom other enzymatic deficiencies have been excluded.

Cerebrotendinous Xanthomatosis Presenting with Infantile Spasms and Intellectual Disability

Cerebrotendinous xanthomatosis (CTX) is an inborn error of metabolism leading to progressive multisystem disease. Symptoms often begin in the first decade of life with chronic diarrhea, cataracts, developmental delay, intellectual disability, and cerebellar or pyramidal dysfunction. Later manifestations include tendon xanthomas, polyneuropathy, and abnormal neuroimaging. Pathogenic biallelic variants in CYP27A1 leading to compromised function of sterol 27-hydroxylase result in accumulation of detectable toxic intermediates of bile acid synthesis rendering both genetic and biochemical testing effective diagnostic tools. Effective treatment with chenodeoxycholic acid is available, making early diagnosis critical for patient care. Here we report a new patient with CTX and describe the early signs of disease in this patient. Initial symptoms included infantile spasms, which have not previously been reported in CTX. Developmental delay, mild intellectual disability with measured cognitive decline in childhood, was also observed. These clinical signs do not traditionally compel testing for CTX, and we highlight the need to consider this rare but treatable disorder among the differential diagnosis of children with similar clinical presentation. Increased awareness of early signs of CTX is important for improving time to diagnosis for this patient population.

Optic neuropathy in late-onset neurodegenerative Chédiak–Higashi syndrome

Background The classic form of Chédiak–Higashi syndrome (CHS), an autosomal recessive disorder of lysosomal trafficking with childhood onset caused by mutations in LYST, is typified ophthalmologically by ocular albinism with vision loss attributed to foveal hypoplasia or nystagmus. Optic nerve involvement and ophthalmological manifestations of the late-onset neurodegenerative form of CHS are rarely reported and poorly detailed. Methods Case series detailing ophthalmological and neurological findings in three adult siblings with the late-onset form of CHS. Results All three affected siblings lacked features of ocular albinism and demonstrated significant optic nerve involvement as evidenced by loss of colour and contrast vision, central visual field loss, optic nerve pallor, retinal nerve fibre layer thinning by optical coherence tomography (OCT) and abnormal visual evoked potential, with severity corresponding linearly to age of the sibling and severity of neurological disease. Further, unusual prominence of a ‘third line’ on macular OCT that may be due to abnormal melanosomes was seen in all three siblings and in their father. Neurological involvement included parkinsonism, cerebellar ataxia and spastic paraparesis. Conclusions This report expands the ophthalmological phenotype of the late-onset neurodegenerative form of CHS to include optic neuropathy with progressive vision loss, even in the absence of ocular albinism, and abnormal prominence of the interdigitation zone between cone outer segment tips and apical processes of retinal pigment epithelium cells on macular OCT.

Co-occurrence of the Poland sequence in a patient with the cobalamin C defect: more than just a coincidence?

A newborn male born to a non-consanguineous Mexican couple was evaluated for lethargy and elevated C3 acylcarnitine (18 μmol/L, normal <5) on newborn screening. Plasma homocysteine, methionine, and methylmalonic acid (MMA) were 272.4 (normal 5–15), 5 μmol/L (normal 10– 60 nmol/L), and 85 μmol/L (normal <0.8 μmol/L), respectively. Molecular analysis of MMACHC revealed compound heterozygosity for a novel, maternally-inherited deletion encompassing exons 2–4 and a c.615C>G (p.Y205X) mutation, confirming the cobalamin C defect (cblC; OMIM 277400). Chromosomal microarray was normal. Antenatal history was uneventful without maternal substance abuse. Asymmetry of the anterior chest wall was noted, with severe hypoplasia of the right pectoralis major muscle and an inverted right nipple. Poland sequence (PS, OMIM 173800) is characterized by unilateral hypoplasia of pectoralis muscles, often with associated ipsilateral symbrachydactyly (McGillivray and Lowry 1977), and is usually sporadic. Pathogenesis may involve an early embryonic vascular disruption event causing local or segmental tissue hypoxia (Bavinck and Weaver 1986). Observation of PS following maternal hyperhomocysteinemia or antenatal cocaine/prostaglandin exposure, and affecting right subclavian artery territory structures support a vascular hypothesis (Puvabanditsin et al 2005; Franceschini et al 2002). Massive hyperhomocysteinemia prior to treatment initiation is typical in cblC, and pulmonary hypertension, congenital heart defects, and microangiopathic renal disease are common (Profitlich et al 2009; CarrilloCarrasco et al 2012). Observed congenital anomalies in cblC may be partially attributable to defective folate remethylation, hypomethioninemia, or MMA cytotoxicity. Co-occurrence of PS and cblC is extremely unlikely by chance alone (incidences 1/20,000 and 1/100,000, respectively), and this case expands the spectrum of physical anomalies observed in cblC, highlighting associations between early vascular development, methylation events in utero , and potential etiopathogenetic mechanisms of PS.

Neonatal Onset Interstitial Lung Disease as a Primary Presenting Manifestation of Mucopolysaccharidosis Type I

We describe two cases of neonatal onset interstitial lung disease eventually diagnosed as mucopolysaccharidosis type I (MPS I). In both cases, evaluation led to lung biopsy, pathology review, and identification of glycogen deposition. Pulmonary interstitial glycogenosis (PIG) was considered as a clinical diagnosis in case one; however, further review of electron microscopy (EM) was more consistent with MPS I rather than PIG. Both cases were confirmed to have MPS I by enzyme and molecular analysis. Neonatal interstitial lung disease is an atypical presentation for MPS I which is likely under-recognized. Diagnosis through clinical guidelines and a multidisciplinary approach had a major impact on patient management. The diagnosis of MPS I prompted timely initiation of enzyme replacement therapy (ERT) and the patients ultimately underwent hematopoietic stem cell transplantation (HSCT) to improve symptomatic outcomes. In addition to treatment, immediate precautionary recommendations were made to avoid potentially catastrophic outcomes associated with cervical instability. These cases add to the clinical spectrum of MPS I in the newborn period. They further illustrate the difficulties in early recognition of the disease, and importance of a definitive diagnosis of MPS I in infants with interstitial lung disease.

Lethal neonatal hyperammonemia in severe ornithine transcarbamylase (OTC) deficiency compounded by large hepatic portosystemic shunt

A term male infant presented at 48 h of age with apnea, lethargy, and seizures. Plasma ammonia was 1180 μmol/ L, and biochemical studies (plasma citrulline <2 μM; urine orotate 1142 μg/ng creatinine) were consistent with a proximal urea cycle disorder (UCD). Initially, hyperammonemia improved with continuous renal replacement therapy (cRRT) and ammonia scavengers. Upon discontinuation of cRRT, hyperammonemia worsened and lactic acidosis developed, with coexistent fulminant hepatic and renal failure. Color Doppler ultrasound of the liver (Fig. 1a–d identified a large congenital intrahepatic portosystemic shunt (PSS) with enlarged middle hepatic vein (MHV) with abnormal tortuous portosystemic shunt to the left portal vein (LPV). Congenital PSS occurs in approximately 1:25,000 births and is classified as either intraor extrahepatic (Stringer 2008). Shunts bypassing hepatic circulation can be associated with hyperammonemia and encephalopathy, even in the setting of normal urea cycle function (Witters et al. 2008; Kim et al. 2012; Sokollik et al. 2013; Van Straten et al. 2014). Plasma glutamine was initially massively elevated (>3000 μM), but it normalized with cRRT and ammonia scavengers despite persistence of recalcitrant hyperammonemia. OTC deficiency was confirmed by identification of a 4.3-Mb hemizygous deletion involving Xp21.1–Xp11.4 and incorporating the entire OTC locus, portending absent functional OTC enzymes and severe disease. The hemizygous Xp deletion, also involving other key genes (including CYBB and XK, associated with chronic granulomatous disease and McLeod syndrome, respectively), together with the PSS, caused recalcitrant, fatal hyperammonemia and lactic acidosis off cRRT. Autopsy revealed extensive hepatic centrilobular necrosis and dilated vascular spaces. This case illustrates the devastating effects of hepatic vascular anomalies in patients with coexistent UCD.

Rapid resolution of infantile lipemia retinalis following exchange transfusion

A 7-week-old female presented with irritability, emesis, fever, and feeding intolerance. She had severe hypertriglyceridemia (15078mg/dL), hypercholesterolemia (1807 mg/dL), elevated lipase (1533 U/L), and hepatomegaly. Retinal vasculature had a milky pink appearance, consistent with grade III lipemia retinalis (LR), (Fig. 1a-b) with grossly lipemic blood (Fig. 1c-d). Because of the presumed diagnosis of lipoprotein lipase (LPL) deficiency and clinical suspicion for pancreatitis, double exchange transfusion (ET) was undertaken and stabilized dyslipidemia. Repeat funduscopic photographs three days following ET (triglycerides 1284 mg/dL) revealed resolution of LR (Fig. 1e-f). LPL sequencing showed a homozygous pathogenic missense mutation (c.644G>A; p.G215E), confirming the diagnosis of LPL deficiency. LPL deficiency is a rare autosomal recessive disorder of chylomicron clearance associated with severe dyslipidemia and hypertriglyceridemia (Zahavi et al 2013; Brunzell 2014). LR occurs when plasma triglycerides exceed 2000 mg/dL. Grade III LR, the most severe form, is characterized by salmon-colored retina with milky retinal vasculature. LR has not been associated with changes in visual acuity, but recent data suggests electroretinographic changes can occur (Zahavi et al 2013; Cypel et al 2008; Lu et al 2005; Fu et al 2014). We employed ET based on clinical experience in similar conditions and another published case demonstrating its utility in infantile LPL deficiency (Pugni et al 2014). Salient features of this case are rapid improvement of pancreatitis and dyslipidemic parameters in conjunction with documented rapid resolution of LR following ET. The patient remains stable with triglycerides consistently <2000 mg/dL on total restriction of dietary long chain triglycerides.