Exons deletion of CNKSR2 gene identified in X-linked syndromic intellectual disability.

BACKGROUND: The Houge type of X-linked syndromic mental retardation is an X-linked intellectual disability (XLID) recently recorded in the Online Mendelian Inheritance in Man (OMIM) and only 8 cases have been reported in literature thus far. CASE PRESENTATION: We present two brothers with intractable seizures and syndromic intellectual disability with symptoms consisting of delayed development, intellectual disability, and speech and language delay. The mother was a symptomatic carrier with milder clinical phenotype. Whole exome sequencing identified a small fragment deletion spanning four exons, about 9.5 kilobases (kb) in length in the CNKSR2 gene in the patients. The mutation co-segregation revealed that exon deletions occurred de novo in the proband's mother. CONCLUSION: Although large deletions have been reported, no small deletions have yet been identified. In this case report, we identified a small deletion in the CNKSR2 gene. This study enhances our knowledge of the CNKSR2 gene mutation spectrum and provides further information about the phenotypic characteristics of X-linked syndromic intellectual disability.

Neonatal Hypocalcemic Seizures in Offspring of a Mother With Familial Hypocalciuric Hypercalcemia Type 1 (FHH1).

CONTEXT: Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR) and is considered a benign condition associated with mild-to-moderate hypercalcemia. However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy. OBJECTIVE: The objective of this work is to characterize the range of calcitropic phenotypes in the children of a mother with FHH1. METHODS: A 3-generation FHH kindred was assessed by clinical, biochemical, and mutational analysis following informed consent. RESULTS: The FHH kindred comprised a hypercalcemic man and his daughter who had hypercalcemia and hypocalciuria, and her 4 children, 2 of whom had asymptomatic hypercalcemia, 1 was normocalcemic, and 1 suffered from transient neonatal hypocalcemia and seizures. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (6.28 mg/dL); normal, 2.0 to 2.8 mmol/L (8.0-11.2 mg/dL) and parathyroid hormone of 2.2 pmol/L; normal 1.0 to 9.3 pmol/L, and required treatment with intravenous calcium gluconate infusions. A novel heterozygous p.Ser448Pro CaSR variant was identified in the hypercalcemic individuals, but not the children with hypocalcemia or normocalcemia. Three-dimensional modeling predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction within the CaSR extracellular domain. The variant Pro448 CaSR, when expressed in HEK293 cells, significantly impaired CaSR-mediated intracellular calcium mobilization and mitogen-activated protein kinase responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation. CONCLUSIONS: Thus, children of a mother with FHH1 can develop hypercalcemia or transient neonatal hypocalcemia, depending on the underlying inherited CaSR mutation, and require investigations for serum calcium and CaSR mutations in early childhood.

Diagnosis of seizures and encephalopathy using conventional EEG and amplitude integrated EEG.

Seizures are more common in the neonatal period than at any other time of life, partly due to the relative hyperexcitability of the neonatal brain. Brain monitoring of sick neonates in the NICU using either conventional electroencephalography or amplitude integrated EEG is essential to accurately detect seizures. Treatment of seizures is important, as evidence increasingly indicates that seizures damage the brain in addition to that caused by the underlying etiology. Prompt treatment has been shown to reduce seizure burden with the potential to ameliorate seizure-mediated damage. Neonatal encephalopathy most commonly caused by a hypoxia-ischemia results in an alteration of mental status and problems such as seizures, hypotonia, apnea, and feeding difficulties. Confirmation of encephalopathy with EEG monitoring can act as an important adjunct to other investigations and the clinical examination, particularly when considering treatment strategies such as therapeutic hypothermia. Brain monitoring also provides useful early prognostic indicators to clinicians. Recent use of machine learning in algorithms to continuously monitor the neonatal EEG, detect seizures, and grade encephalopathy offers the exciting prospect of real-time decision support in the NICU in the very near future.

Seizure classification, etiology, and management.

The first weeks of life are a time of heightened risk for seizures due to age-dependent physiologic features of the developing brain that lead to increased neuronal excitation and decreased inhibition. Usually, seizures in neonates are a symptom of an acute brain injury; seizures are only rarely due to neonatal-onset epilepsy syndromes. Neonatal seizures are harmful to the developing brain; early and accurate diagnosis is critical. For suspected seizures, EEG monitoring should be initiated as soon as is feasible, in order to evaluate for events of concern, screen for subclinical seizures, and assess the EEG background. Amplitude-integrated EEG can provide excellent complementary data, particularly with regard to evolution of background patterns, but has limited sensitivity to detect individual neonatal seizures. An urgent and systematic approach to precise etiologic diagnosis is key for optimal management and estimates of prognosis. Evaluation of the seizure etiology must occur in parallel with initiation of appropriate treatment. It is critical that neonatologists and neurologists develop hospital-specific, consensus-based practice pathways for neonatal seizure evaluation and treatment. Such practice pathways can streamline medical decision making, facilitate rapid medication administration, and potentially decrease seizure burden and optimize outcomes. Herein, the pathophysiology, epidemiology, treatment, and long-term management considerations for neonatal seizures are presented.

Outcome in preterm infants with seizures.

Most neonatal seizures in preterm newborns are of acute symptomatic origin with a prevalence higher than in full-term infants. To date, recommendations for management of seizures in preterm newborns are scarce and do not differ from those in full-term newborns. Mortality in preterm newborns with seizures has significantly declined over the last decades, from figures of 84%-94% in the 1970s and 1980s to 22%-45% in the last years. However, mortality is significantly higher in those with a birth weight<1000g and a gestational age<28 weeks. Seizures are a strong predictor of unfavorable outcomes, including not only cerebral palsy, epilepsy, and intellectual disability, but also vision, hearing impairment, and microcephaly. The majority of patients with developmental delay are severely affected and this is usually associated with cerebral palsy. Furthermore, the incidence of epilepsy after neonatal seizures seems to be lower in preterm than in full-term infants but the risk is approximately 40 times greater than in the general population. Clinical studies cannot disentangle the specific and independent contributions of seizure-induced functional changes and the role of etiology and brain damage severity in determining the long-term outcomes in these newborns.

The Clinical and Molecular Characteristics of Molybdenum Cofactor Deficiency Due to MOCS2 Mutations.

BACKGROUND: We explored the clinical and molecular characteristics of molybdenum cofactor deficiency due to MOCS2 muations. METHODS: We summarize the genetic and clinical findings of previously reported patients with a MOCS2 mutation. We also present a new patient with novel neuroradiological findings associated with molybdenum cofactor deficiency due to a novel homozygous variant in the 5' untranslated region of the MOCS2 gene. RESULTS: The study population comprised 35 patients with a MOCS2 gene mutation. All reported children had delayed motor milestones. The major initial symptom was seizures in neonatal period. Facial dysmorphism was present in 61% of the patients. Only one patient had ectopia lentis. Agenesis of the corpus callosum and an associated interhemispheric cyst in our case are novel neuroradiological findings. CONCLUSIONS: The occurrence of neonatal seizures and feeding difficulties can be the first clinical signs of molybdenum cofactor deficiency. Although there is no effective therapy for this condition, early diagnosis and genetic analysis of these lethal disorders facilitate adequate genetic counseling.

CNTNAP1-Related Congenital Hypomyelinating Neuropathy.

BACKGROUND: Congenital hypomyelinating neuropathy is a rare form of hereditary peripheral neuropathy characterized by nonprogressive weakness, areflexia, hypotonia, severely reduced nerve conduction velocities, and hypomyelination. Mutations in contactin-associated protein 1 (CNTNAP1) were recently described as a cause of congenital hypomyelinating neuropathy. CNTNAP1-associated congenital hypomyelinating neuropathy is characterized by severe hypotonia, multiple distal joint contractures, and high mortality in the first few months of life. METHODS: Whole-exome sequencing was performed in two siblings with congenital hypotonia. Detailed phenotyping data were compared with previously reported cases. RESULTS: A novel, heterozygous compound mutation of CNTNAP1 was identified in both siblings. We also reviewed 17 patients harboring 10 distinct mutations from previously published studies. All patients presented with severe hypotonia, respiratory distress, and multiple cranial nerve palsies at birth. Six of 19 patients survived beyond infancy and required chronic mechanical ventilation. Seizures were common in the surviving patients. CONCLUSIONS: These findings suggest that CNTNAP1-related congenital hypomyelinating neuropathy is a distinct form of hereditary neuropathy that affects both the central and peripheral nervous systems with no clear phenotype-genotype correlation. Our findings also indicate that arthrogryposis multiplex congenita and early lethality are not universal outcomes for patients with congenital hypomyelinating neuropathy.

Neonatal Sleep-Wake Analyses Predict 18-month Neurodevelopmental Outcomes.

Objectives: The neurological examination of critically ill neonates is largely limited to reflexive behavior. The exam often ignores sleep-wake physiology that may reflect brain integrity and influence long-term outcomes. We assessed whether polysomnography and concurrent cerebral near-infrared spectroscopy (NIRS) might improve prediction of 18-month neurodevelopmental outcomes. Methods: Term newborns with suspected seizures underwent standardized neurologic examinations to generate Thompson scores and had 12-hour bedside polysomnography with concurrent cerebral NIRS. For each infant, the distribution of sleep-wake stages and electroencephalogram delta power were computed. NIRS-derived fractional tissue oxygen extraction (FTOE) was calculated across sleep-wake stages. At age 18-22 months, surviving participants were evaluated with Bayley Scales of Infant Development (Bayley-III), 3rd edition. Results: Twenty-nine participants completed Bayley-III. Increased newborn time in quiet sleep predicted worse 18-month cognitive and motor scores (robust regression models, adjusted r2 = 0.22, p = .007, and 0.27, .004, respectively). Decreased 0.5-2 Hz electroencephalograph (EEG) power during quiet sleep predicted worse 18-month language and motor scores (adjusted r2 = 0.25, p = .0005, and 0.33, .001, respectively). Predictive values remained significant after adjustment for neonatal Thompson scores or exposure to phenobarbital. Similarly, an attenuated difference in FTOE, between neonatal wakefulness and quiet sleep, predicted worse 18-month cognitive, language, and motor scores in adjusted analyses (each p < .05). Conclusions: These prospective, longitudinal data suggest that inefficient neonatal sleep-as quantified by increased time in quiet sleep, lower electroencephalogram delta power during that stage, and muted differences in FTOE between quiet sleep and wakefulness-may improve prediction of adverse long-term outcomes for newborns with neurological dysfunction.

Neonatal venlafaxine discontinuation syndrome: A mini-review.

During pregnancy, the developing fetal brain may be exposed to a range of psychotropic medications. The serotonin-noradrenergic reuptake inhibitor venlafaxine is one such drug, when used as a maternal antidepressant. Here we review the discontinuation phenomenon that may follow in exposed neonates following birth. Adults who abruptly stop taking venlafaxine can experience withdrawal symptoms. Venlafaxine and its metabolites cross the placenta and so the newborn can be exposed to this risk, as well as potential toxicity. Several case reports document features of encephalopathy following birth in exposed neonates. It is suggested that a possible combination of partial toxicity together with withdrawal may lead to these symptoms - a discontinuation syndrome. The underlying neurobiology is not yet established. Common symptoms and signs seen in affected neonates include poor feeding, jitteriness, respiratory distress and myoclonic seizure-like activity. Onset is typically between birth and day 4 of life with resolution by 2-21 days of life. Electroencephalography does not necessarily correlate with clinical seizures, or response to anticonvulsants. In limited follow-up data, no long-term consequences of this discontinuation syndrome are reported. We suggest where it is not possible for mothers to be switched from venlafaxine to other antidepressant drugs, that their infants are observed closely for 2-4 days following delivery. In symptomatic neonates, following exclusion of other causes, supportive care including breastfeeding may be sufficient for management. Clinicians should be vigilant to venlafaxine discontinuation as a cause for encephalopathy or paroxysmal episodes in exposed neonates.

Placental histologic patterns and neonatal seizure, in preterm premature rupture of membrane.

OBJECTIVE: To investigate the relationship between placenta and perinatal outcomes, in preterm infants born to mothers with preterm premature rupture of fetal membrane (PPROM). METHODS: We report detailed histology of placentas and perinatal outcomes of infants from 79 PPROM pregnancies. Placental histologic pattern and adverse perinatal outcomes were assessed by logistic regression, adjusting for gestational age at birth, birth weight and interval from rupture of membrane to delivery. RESULTS: Mean gestational age at membrane rupture was 29.5 ± 3.4 weeks. The incidence of histologic chorioamnionitis (HCA), fetal inflammatory response (FIR) and vascular thrombotic abnormalities in placental histologic examination were 63.3, 25.3 and 78.5%, respectively. Neonates with FIR showed significantly higher incidence of periventricular leukomalacia (PVL) (85% versus 59.3%, p = 0.0364) at brain ultrasonography, than neonates without FIR, in univariate analysis, but not in logistic regression analysis. In logistic regression analysis, the odds ratio of low Apgar score at 1 min in the neonates with clinical chorioamnionitis was 5.009 (95% CI, 1.242-20.195). The odds ratio of neonatal seizure in the neonates with FIR and vascular thrombotic problem was 7.486 (95% CI, 1.617-34.653). CONCLUSIONS: Our findings support the association between FIR with vascular thrombotic problem in placenta and neonatal seizure, in pregnancies with PPROM.

Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.

Mutations in PIGN, resulting in multiple congenital anomalies-hypotonia-seizures syndrome, a glycosylphosphatidylinositol anchor deficiency, have been published in four families to date. We report four patients from three unrelated families with epilepsy and hypotonia in whom whole exome sequencing yielded compound heterozygous variants in PIGN. As with previous reports Patients 1 and 2 (full siblings) have severe global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features, including high palate, bitemporal narrowing, depressed nasal bridge, and micrognathia; Patient 3 had early global developmental delay with later progressive spastic quadriparesis, intellectual disability, and intractable generalized epilepsy; Patient 4 had bilateral narrowing as well but differed by the presence of hypertelorism, markedly narrow palpebral fissures, and long philtrum, had small distal phalanges of fingers 2, 3, and 4, absent distal phalanx of finger 5 and similar toe anomalies, underdeveloped nails, unusual brain anomalies, and a more severe early clinical course. These patients expand the known clinical spectrum of the disease. The severity of the presentations in conjunction with the patients' mutations suggest a genotype-phenotype correlation in which congenital anomalies are only seen in patients with biallelic loss-of-function. In addition, PIGN mutations appear to be panethnic and may be an underappreciated cause of epilepsy.

Pilot evaluation of the population pharmacokinetics of bumetanide in term newborn infants with seizures.

Recent experimental data suggest bumetanide as a possible therapeutic option in newborn infants with seizures after birth asphyxia. Because pharmacokinetic (PK) data are lacking in this population, who very often benefit from therapeutic cooling, which can modify the PK behavior of a drug, a PK study was conducted in term infants with seizures caused by hypoxic-ischemic encephalopathy. Fourteen infants were included, 13 of them being cooled. Forty-nine blood samples were available for the determination of the plasma concentration of bumetanide. Concentration-time data were analyzed by the use of a population approach performed with Monolix Software. Bumetanide was found to follow a 2-compartment model. The mean values were 0.063 L/h for clearance, 0.28 and 0.44 L for the central and peripheral distribution volumes, respectively, and 0.59 L/h for the distribution clearance. Birth body weight explained the interindividual variability of bumetanide clearance via an allometric model. No relationship was found between bumetanide exposure and its efficacy (reduction in seizure burden) or its toxicity (hearing loss). This study describes the first PK model of bumetanide in hypothermia-treated infants with seizures.

Magnetic resonance imaging and computed tomography findings of Dyke-Davidoff-Masson-like syndrome in a cat.

CASE REPORT: A 3.5-year-old spayed female Domestic Shorthair cat was evaluated for new onset seizures and lateralising signs indicative of a lesion in the right prosencephalon. Magnetic resonance imaging and computed tomography of the head revealed hypoplasia of the right cerebral hemisphere and changes in the overlying cranium, including hyperostosis and expansion of the diploic space, resulting in an increased pneumatisation of the rostral bones of the cranium. A congenital injury to the cerebral hemisphere and secondary changes of the cranium in response to the decreased brain parenchyma was presumed. Similar changes have been previously recognised in human patients with unilateral anomalies of the cerebral hemispheres, termed Dyke-Davidoff-Masson syndrome (DDMS). CONCLUSION: The case presented is the first clinical and imaging description of a cat with a syndrome that closely resembles DDMS in humans. The description of the syndrome allows recognition of an additional differential for seizures in a young patient and informs the clinician of the imaging characteristics of the cranium seen with early loss of brain parenchyma.

A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts.

N-Glycanase 1, encoded by NGLY1, catalyzes the deglycosylation of misfolded N-linked glycoproteins retrotranslocated into the cytosol. We identified nine cases with mutations in NGLY1. The patients show developmental delay, seizures, peripheral neuropathy, abnormal liver function and alacrima (absence of tears). The mutations in NGLY1 resulted in the absence of N-glycanase 1 protein in patient-derived fibroblasts. Applying a recently established cellular deglycosylation-dependent Venus fluorescence assay, we found that patient fibroblasts had dramatically reduced fluorescence, indicating a pronounced reduction in N-glycanase enzymatic activity. Using this assay, we could find no evidence of other related activities. Our findings reveal that NGLY1 mutations destroy both N-glycanase 1 protein and enzymatic activity.

Elejalde syndrome (ES).

Silvery hair and severe dysfunction of the central nervous system (Neuroectodermal melanolysosomal disease or Elejalde Syndrome) characterize this rare autosomal recessive syndrome. The main clinical features include silver-leaden hair, bronze skin after sun exposure, and neurologic involvement. Large granules of melanin unevenly distributed in the hair shaft are observed. Abnormal melanocytes and melanosomes and abnormal inclusion bodies in fibroblasts may be present. We report a 10-year-old girl with silver-leaden (silvery) hair, bronze skin color on sun-exposed areas, generalized hypopigmentation of covered body parts, and congenital seizures. The child was the elder of two children born of a consanguineous marriage. The younger sibling, a female neonate, had the same clinical presentation.

Low Apgar score, neonatal encephalopathy and epidural analgesia during labour: a Swedish registry-based study.

BACKGROUND: Maternal intrapartum fever (MF) is associated with neonatal sequelae, and women in labour who receive epidural analgesia (EA) are more likely to develop hyperthermia. The aims of this study were to investigate if EA and/or a diagnosis of MF were associated to adverse neonatal outcomes at a population level. METHODS: Population-based register study with data from the Swedish Birth Register and the Swedish National Patient Register, including all nulliparae (n=294,329) with singleton pregnancies who gave birth at term in Sweden 1999-2008. Neonatal outcomes analysed were Apgar score (AS)<7 at 5 min and ICD-10 diagnosis of neonatal encephalopathy (e.g. convulsions or neonatal cerebral ischaemia). Multivariate logistic regression was used to calculate adjusted odds ratios (AOR) with 95% confidence intervals (CI). RESULTS: EA was used in 44% of the deliveries. Low AS or encephalopathy was found in 1.26% and 0.39% of the children in the EA group compared with 0.80% and 0.29% in the control group. In multivariate analysis, EA was associated with increased risk with low AS, AOR 1.27 (95% CI 1.16-1.39), but not with diagnosis of encephalopathy, 1.11 (0.96-1.29). A diagnosis of MF was associated with increased risk for both low AS, 2.27 (1.71-3.02), and of neonatal encephalopathy, 1.97 (1.19-3.26). CONCLUSION: Diagnosis of MF was associated with low AS and neonatal encephalopathy, whereas EA was only associated with low AS and not with neonatal encephalopathy. The found associations might be a result of confounding by indication, which is difficult to assess in a registry-based population study.

Discinesia paroxística cinesigénica familiar: descripción de una familia / Familial paroxysmal kinesigenic dyskinesia. A case description

Las discinesias paroxísticas son trastornos del movimiento caracterizadas por episodios repentinos de movimientos involuntarios. Se dividen en cinesigénicas, no cinesigénicas e inducidas por el ejercicio. Los autores enfatizan la importancia de la historia clínica y de la descripción de los episodios en el diagnóstico diferencial. Adolescente de 12 años con episodios de torsión de la lengua y posturas distónicas de las extremidades superiores desencadenados por movimientos súbitos como empezar a correr o bajar escaleras y al comienzo del ejercicio, cesando espontáneamente segundos después. Algunos episodios eran desencadenados por el estrés. En la historia familiar, el padre, tío paterno y hermana también presentaban episodios paroxísticos. El examen neurológico intercrítico fue normal. Se identificó una mutación en el gen PRRT2 asociado con trastornos neurológicos como discinesia paroxística cinesigénica, convulsiones infantiles con coreoatetosis, migraña, ataxia episódica, tortícolis paroxística y retraso cognitivo. El tratamiento con carbamacepina fue eficaz

Paroxysmal dyskinesias are movement disorders characterized by sudden episodes of involuntary movements. They are divided into kinesigenic, non-kinesigenic, and exerciseinduced dyskinesias. Emphasis is made on the importance of the clinical history and fully describing the episodes in the differential diagnosis. The case is presented of a twelve year-old female with paroxysmal episodes of tongue torsion and dystonic postures of the upper limbs when start running or descending stairs and in the beginning of physical exercise, which ceased spontaneously seconds later. Some episodes were triggered by stress. In family history her father, paternal uncle, and sister also had paroxysmal movements. Interictal neurological examination was normal. Laboratory tests revealed a mutation in PRRT2 gene, which is related to neurological disorders such as paroxysmal kinesigenic dyskinesia, infantile convulsions and choreoathetosis migraine, episodic ataxia, paroxysmal torticollis, and intellectual disability. Treatment with carbamazepine was effective

Case report of a de novo brainstem arteriovenous malformation in an 18-year-old male and review of the literature.

De novo intracerebral arteriovenous malformations (AVMs) are exceedingly rare with only seven reported cases in the literature. Although generally considered congenital by nature, the lesions do not manifest themselves clinically until the third or fourth decades of life. However, with the advent of improved imaging modalities and more frequent surveillance, an increasing number of de novo cases are being found challenging the concept AVMs develop in the perinatal/antenatal period. Alternatively, this phenomenon could represent a distinct entity in which lesion development occurs after birth. A PubMed search of "de novo cerebral arteriovenous malformation" was performed in which seven reported cases were found. The mean age at diagnosis was 14.7 years with a mean follow-up imaging study of 5.8 years. Lesion location was supratentorial in all previously described cases. This case involves an 18-year-old male with congenital hydrocephalus and seizures diagnosed at 7 months of age. The patient underwent a ventriculoperitoneal shunt and was followed frequently by a neurologist. The last diagnostic imaging was an unremarkable MRI of the brain at age 12. Seven years later, the patient presented with an intracerebral hemorrhage. A CT angiogram demonstrated a large brainstem AVM with an intraparenchymal hemorrhage and intraventricular extension. This case is unique in that it is the first infratentorial de novo AVM. The congenital nature of AVMs is challenged with the increasingly described series of patients with previously documented normal radiographic imaging. This suggests there may be a subset of patients genetically predisposed to postnatal development of AVMs.

First case report of short-chain acyl-CoA dehydrogenase deficiency in China.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive inborn error of mitochondrial fatty acid oxidation. It is caused by rare mutations as well as polymorphic susceptibility variants. We describe here the case of a 1-year-old male patient who had growth and mental retardation, seizures, and recurring fever since infancy. Urinary gas chromatography/mass spectrometry (GC/MS) showed elevated levels of ethylmalonic acid. Plasma acylcarnitines on tandem mass spectrometry (MS/MS) and elevations of C4-cartinitine are consistently present. The two polymorphic susceptibility variants of the short-chain acyl-CoA dehydrogenase (SCAD) gene, c.625G>A and c.322G>A, were detected. Because of its highly variable clinical characteristics, there are no related reports in China. This report broadens the phenotype and genotype of SCADD in China and underlines the difficulty of diagnosis.

L-2-hydroxyglutaric aciduria in two female Yorkshire terriers.

Two female Yorkshire terrier puppies were presented with generalized tonic-clonic seizures and ataxia. MRI revealed bilaterally symmetrical, diffuse regions of gray matter hyperintensity on T2-weighted and fluid-attenuated inversion recovery sequences. Urinary organic acids were quantified by gas chromatography-mass spectroscopy and were consistent with a diagnosis of L-2-hydroxyglutaric aciduria (L2HGA). The L2HGDH gene encodes for the enzyme L-2-hydroxyglutarate dehydrogenase, which helps break down L-2-hydroxyglutaric acid. In both puppies described in this report, a homozygous mutation at the translation initiation codon of the homolog canine L2HGDH gene was detected (c.1A>G; p.Met1?), confirming the diagnosis of L2HGA at the DNA level. Canine L2HGA is caused by more than one mutation of L2HGDH, as reported in humans.