Unusual biochemical and clinical features in a girl with ornithine transcarbamylase deficiency

A girl, ultimately diagnosed as having profound ornithine transcarbamylase (OTC) deficiency, presented as a neonate with feeding intolerance, irritability, and seizures without concurrent hyperammonemia. Developing normally until ten months of age, the girl subsequently experienced two episodes of hyperammonemia, which were associated with focal seizures and residual hemiparesis. She continued to have profound neurologic impairment and seizures and died at 26 months of age, despite appropriate dietary protein restriction, sodium benzoate, and arginine supplementation. Symptomatic OTC deficiency has not been previously reported unassociated with hyperammonemia. The recurrent cerebrovascular episodes are distinctly uncommon in patients with urea cycle enzymopathies.     

An autopsy case of ornithine transcarbamylase deficiency

We present an autopsy case of ornithine transcarbamylase (OTC) deficiency with grumose degeneration in the dentate nucleus of the cerebellum. The patient had intractable neonatal convulsions and hyperammonemia from the 3rd day after birth. Diagnosis of OTC deficiency was made based on null activity of the enzyme and four-base deletions in exon 9 of the OTC gene. Death was due to sepsis as well as disseminated intravascular coagulation at 1 year and 2 months of age. Neuropathology showed multiple cystic changes and ulegyria in the bilateral frontal and parietal lobes. Multiple cysts were associated with the region, which was infiltrated with macrophages surrounded by astroglia showing palisading pattern. Ferrugination was marked in the thalamus and severe neuronal loss with astrogliotic change in the CA1-2 area of the hippocampus. Grumose degeneration was noted in the dentate nucleus of the cerebellum. This is the first report of grumose degeneration in OTC deficiency.     

Severe cerebral damage in ornithine transcarbamylase deficiency

Two patients are described with hyperammonemia due to ornithine transcarbamylase (OTC) deficiency who suffered severe shrinkage and collapse of the brain. The cerebral cortex was spongy and cavitated, containing only a few residual neurons, and was markedly gliosed. In one patient the basal ganglia were affected and harbored Alzheimer type II astrocytes. These lesions resemble those of acquired hepatocerebral degeneration and occur especially in female children with the milder form of the disease, who have a potential to survive. Strict observance of dietary restrictions is mandatory to avoid catastrophic damage to the brain.     

Hereditary homozygous heparin cofactor II deficiency and the risk of developing venous thrombosis.

Heparin cofactor II (HCII) is a specific inhibitor of thrombin in the presence of heparin or dermatan sulphate. Although there have been reports on families in which a heterozygous HCII deficiency is associated with thromboembolic events, several epidemiological studies revealed that heterozygous HCII deficiency is as prevalent among healthy subjects as it is among patients with deep venous thrombosis (DVT). It is therefore not yet clear whether HCII is or is not a thrombotic risk factor. We analyze and describe in an extended family the biochemical and genetic thrombophilic risk factors and evaluate the potential thrombotic risk involved in homozygous and heterozygous HCII deficiency, either alone or associated with other thrombotic or circumstantial risk factors. The propositus has had three episodes of DVT and a pulmonary embolism. During the first episode of DVT the patient was diagnosed as having AT deficiency. Later, a functional and antigenic HCII deficiency, compatible with the homozygous form, was detected. The family study shows that both the propositus and her sister have homozygous HCII deficiency and that 12 of the 27 family members have heterozygous HCII deficiency. This is possibly the first case report on a homozygous phenotype for the HCII deficiency with. in addition, partial AT deficiency. The propositus has suffered several thrombotic events, unlike the other 12 family members with heterozygous HCII deficiency and her sister, who is also homozygous for this disorder. We suggest that HCII deficiency may play a limited in vivo role as a thrombotic risk factor unless associated with AT deficiency or another congenital thrombotic risk factor.     

Urea cycle disorders in adult patients

INTRODUCTION: Urea cycle disorders (UCD) usually present after 24 h to 48 h of life with failure to thrive, lethargy and coma leading to death, but milder forms may occur from infancy to adulthood. STATE OF THE ART: Survival of children with UCD has significantly improved and the need for transitional care to adulthood has emerged. Adult onset UCD present with chronic or acute neurological, psychiatric and digestive symptoms associated with protein avoidance. Ornithine transcarbamylase (OTC) deficiency, which is inherited as an X-linked disorder, is the most well-described UCD in adults. Acute decompensations associate the triad of encephalopathy, respiratory alkalosis and hyperammonemia. Acute encephalopathy is characterized by brain edema, which is life-threatening without treatment. Specific urea cycle enzyme deficiency can be suspected in the presence of abnormal plasma amino acids concentrations and urinary excretion of orotic acid. A measurement enzyme activity in appropriate tissue, or DNA analysis if available, is required for diagnosis. Treatment requires restriction of dietary protein intake and the use of alternative pathways of waste nitrogen excretion with sodium benzoate and sodium phenylbutyrate. Patients with acute forms may need hemodialysis or hemodiafiltration. Therapeutic goals for OTC deficiency are to maintain plasma ammonia<80 micromol/L, plasma glutamine<1,000 micromol/L, argininemia 80-150 micromol/L and branched chain amino acids within the normal range, in order to prevent episodes of potentially lethal acute hyperammonemia. CONCLUSION: Potentially fatal acute hyperammonemia may occur in male or female patients at any age. Ammonia should be measured promptly in case of acute neurological and psychiatric symptoms or coma.     

A case of ornithine transcarbamylase deficiency presenting severe symptoms in adulthood]

An adult female case of ornithine transcarbamylase (OTC) deficiency is presented in the following. The patient had had past episodes of drowsiness with a duration less than a few minutes several times a year during childhood. She suddenly became comatose at 25 years of age, and died after 13 months of persistent vegetative state. Blood chemistry showed hyperammonemia with no liver cirrhosis or portal-systemic shunt. Plasma amino acid analysis indicated elevated glutamate and glycine levels, and plasma levels of citrulline and arginine to be low. The urinary orotic acid level was high. OTC activity of a liver specimen was 65 percent of the normal level. This is a rare case demonstrating hyperglycinemia and an elevated level of serum OTC. The importance of ruling out defective ureagenesis in adults with disturbed consciousness should be emphasized.     

Fatal initial adult-onset presentation of urea cycle defect

BACKGROUND: Ornithine transcarbamylase (OTC) deficiency presents most commonly with neonatal hyperammonemic coma. The gene is on the X chromosome, but the disease may manifest as a dominant trait. Mutations that lead to later-onset presentations may lead to life-threatening disease and may be unrecognized, particularly when the first clinical disease occurs in adulthood. OBJECTIVE: To document the clinical and metabolic consequences of a mutation in the OTC gene. DESIGN: Case reports. SETTING: A metabolic/biochemical genetic referral service. MAIN OUTCOME MEASURES: Clinical and biochemical observations in 3 generations of a family. RESULTS: A mutation in codon 208 of exon 6 in the OTC gene was found in a family in which the proband died of hyperammonemia at 52 years of age. CONCLUSIONS: Diagnosis of late-onset presentations of urea cycle defect in adults may be delayed. Heightened awareness could lead to effective treatment.     

Cardioembolic stroke due to mitral annular calcification with a mobile component]

We report here a 50-year-old man on maintenance hemodialysis who presents right hemiparesis, aphasia. MRI diffusion weighted image showed an increased signal intensity in the area of the left middle cerebral artery. Transthoracic and transesophageal echocardiography revealed a mitral annular calcification (MAC) with a mobile component. After treated with heparin, follow-up echocardiography demonstrated a decrease in the size of the mobile component, but not disappeared. Intraoperative findings showed calcified attachment on the posterior mitral valve. This patient was diagnosed as having cardioembolic stroke due to a MAC with a mobile component.     

Combined genetic defects in a child with ischemic stroke: case report

A 10-year-old Turkish boy was admitted with mild right spastic hermiplegia. First, he experienced sudden numbness and weakness in the right extremities at the age of 2 years and was diagnosed with right hemiparesis. His parents were generally healthy and non-consanguineous. His mother suffered from deep vein thrombosis of the left lower extremity during pregnancy and had recurrent fetal loss. At the age of 10 years, a thrombophilia marker examination revealed that plasma-free protein S was 49.3% (normal range = 70-123%), and factor VIII level was found to be 470 IU/dL (normal = 150 IU/dL). The patient and his two siblings were found to be heterozygous for factor V Leiden mutation. His mother was also heterozygous for factor V Leiden mutation and had protein S deficiency. A combination of protein S deficiency, factor V Leiden mutation, and a high level of factor VIII was detected in our patient. After his first attack at the age of 2 years, in spite of no prophylaxis, he did not experience any other ischemic insult. To our knowledge, this is the first patient with these combinations of genetic defects and ischemic stroke to be reported in the literature.     

Physiological evidence of hypermasculinization in boys with the inattentive type of attention-deficit/hyperactivity disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) is more common in boys than in girls, suggesting that prenatal androgen exposure may play a role in etiology. Click-evoked otoacoustic emissions (CEOAEs) and relative finger length are measures known to exhibit sex differences early in life, also suggesting that prenatal androgen exposure plays a contributing role. CEOAEs and the lengths of the fingers were measured in boys and girls aged 7–15 who were diagnosed as having different types of ADHD. All six possible pairwise length ratios were calculated for the four fingers of each hand. The CEOAEs measured in boys diagnosed as ADHD/Inattentive were substantially smaller than those of either the boys diagnosed as ADHD/Combined or the Control boys, whose mean CEOAEs were alike. Similarly, most of the finger-length ratios (FLRs) were smaller for boys diagnosed as ADHD/Inattentive than for either ADHD/Combined or Control boys. Both of these outcomes represent a hypermasculinization of the boys diagnosed as ADHD/Inattentive. Thus, two quite different physiological measures suggest that these boys diagnosed as ADHD/Inattentive may have been exposed to higher-than-normal levels of androgens at some stage early in development. In accord with both Cantwell's proposal for validating psychiatric disorders and previous suggestions in the literature, these findings support the hypothesis that the Combined and Inattentive groups represent different disorders, not versions of a single disorder.     

Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children

OBJECTIVE: Increasing evidence suggests a significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and restless legs syndrome (RLS). Iron deficiency may underlie common pathophysiological mechanisms in subjects with ADHD plus RLS (ADHD+RLS). To date, the impact of iron deficiency, RLS and familial history of RLS on ADHD severity has been scarcely examined in children. These issues are addressed in the present study. METHODS: Serum ferritin levels, familial history of RLS (diagnosed using National Institutes of Health (NIH) criteria) and previous iron supplementation in infancy were assessed in 12 ADHD+RLS children, 10 ADHD children and 10 controls. RLS was diagnosed using NIH-specific pediatric criteria, and ADHD severity was assessed using the Conners' Parent Rating scale. RESULTS: ADHD symptom severity was higher, although not significantly, in children with ADHD+RLS compared to ADHD. The mean serum ferritin levels were significantly lower in children with ADHD than in the control group (p<0.0005). There was a trend for lower ferritin levels in ADHD+RLS subjects versus ADHD. Both a positive family history of RLS and previous iron supplementation in infancy were associated with more severe ADHD scores. CONCLUSIONS: Children with ADHD and a positive family history of RLS appear to represent a subgroup particularly at risk for severe ADHD symptoms. Iron deficiency may contribute to the severity of symptoms. We suggest that clinicians consider assessing children with ADHD for RLS, a family history of RLS, and iron deficiency.     

A case of carbamoyl phosphate synthetase 1 deficiency presenting symptoms at one month of age

Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is an autosomal recessive disorder of the urea cycle which causes hyperammonemia. Two forms of CPS1D are recognized: a lethal neonatal type and a less severe, delayed onset type. Neonatal CPS1D cases often present their symptoms within the first days of life. Delayed onset type were adolescents or adults, and infantile cases were rare. We report a case of CPS1D in a boy who developed symptoms at one month of age. He showed excellent response to treatments including continuous hemodialysis, drugs and a low-protein diet. His development and weight gain were good at the last follow-up at 1 year and three months of age. Molecular assay of the CPS1 gene demonstrated that the patient was heterozygous for c.2407C>G (R803G: maternal) in exon 20 and c.3784C>T (R1262X: paternal) in exon 32. Our clinical experience suggests that CPS1D could be one of the causes of hyperammonemia in early infantile cases.     

Incidence and diagnosis of anosognosia for hemiparesis revisited

BACKGROUND: In previous studies, the incidence of anosognosia for hemiparesis has varied between 17% and 58% in samples of brain damaged patients with hemiparesis. OBJECTIVE: To determine whether this wide variation might be explained by the different criteria used for diagnosing anosognosia. METHODS: 128 acute stroke patients with hemiparesis or hemiplegia were tested for anosognosia for hemiparesis using the anosognosia scale of Bisiach et al. RESULTS: 94% of the patients who were rated as having "mild anosognosia"-that is, they did not acknowledge their hemiparesis spontaneously following a general question about their complaints-suffered from, and mentioned, other neurological deficits such as dysarthria, ptosis, or headache. However, they immediately acknowledged their paresis when they were asked about the strength of their limbs. Their other deficits clearly had a greater impact. These patients had significantly milder paresis than those who denied their disorder even when asked directly about their limbs. CONCLUSIONS: Patients who do not mention their paresis spontaneously but do so when questioned about it directly should not be diagnosed having "anosognosia." If this more conservative cut off criterion is applied to the data of the present as well as previous studies, a frequency of between 10% and 18% for anosognosia for hemiparesis is obtained in unselected samples of acute hemiparetic stroke patients. The incidence thus seems smaller than previously assumed.     

Treating ADHD: addressing the needs of college students

College students with undiagnosed attention-deficit/hyperactivity disorder (ADHD) exhibit varying symptoms and may have trouble in class, be involved in driving accidents, be late to appointments, be disruptive, and abuse alcohol. Clinicians and others in a position to recognize and identify behaviors indicative of ADHD should either complete a thorough assessment for ADHD, including disorders that commonly co-occur with or are mistaken for the illness, or refer students to someone who can. For students with a comprehensive evaluation who are diagnosed with ADHD, special accommodations are available on campus. Clinicians can provide students with several strategies to manage their disorder and improve their chances of having a successful academic career.     

Functional impairments in adults with self-reports of diagnosed ADHD: A controlled study of 1001 adults in the community

OBJECTIVE: The objective of this study was to evaluate functional impairments in a nonreferred sample of adults identifying themselves as having been diagnosed with attention-deficit/hyperactivity disorder (ADHD) by a clinician in their community. METHOD: We completed a survey in April and May 2003 of a community sample of 500 adults who reported having received a diagnosis of ADHD in the community and 501 gender- and age-matched comparisons from a national sample representative of the U.S. population. RESULTS: Adults with self-reports of diagnosed ADHD in the community were significantly less likely to have graduated high school (83% vs. 93% of controls; p < or = .001) or obtain a college degree (19% vs. 26%; p < .01), were less likely to be currently employed (52% vs. 72%; p < or = .001), and had significantly more mean job changes over 10 years (5.4 vs. 3.4 jobs; p < or = .001). They also were significantly more likely to have been arrested (37% vs. 18% of controls; p < or = .001) or divorced (28% vs. 15%; p < or = .001) and were significantly less satisfied (p < or = .001) with their family, social, and professional lives. CONCLUSION: Adults who reported having received a diagnosis of ADHD in the community had significant impairment in multiple domains of functioning compared with age- and gender-matched controls without this diagnosis, highly consistent with findings derived from carefully diagnosed referred samples.     

A case of spinocerebellar ataxia type 3 (SCA3) associated with isolated ACTH deficiency]

41-year-old woman who was admitted to our hospital because of an acute onset of unconsciousness on October 22, 1999. The level of blood sugar (BS) was 20 mg/dl. A pituitary hormone secretion test detected an isolated deficiency of ACTH. Neurological examinations showed gaze-evoked horizontal nystagmus in the lateral gaze of both eyes, ataxic speech, a slightly wide-based gait and a slight lack of coordination in the four extremities. A cranial MRI revealed moderate atrophy of the pons and the anterior lobe of the cerebellum. The analysis of SCD gene using white blood cells from the patient found that CAG repeat was abnormally prolonged to 74 CAG repeats in the Machado-Joseph disease 1 (MJD1) gene. We compared our patient with 11 reported cases of cerebellar ataxia associated with pituitary gland hormone deficiencies. Compared with 7 patients of the 11, who were reported as having spinocerebellar ataxia or cerebellar ataxia, none of the 7 received gene analysis of SCD and their deficient hormones differed from ours. Three out of the 7 had chorioretinopathy or chorioretinal atrophy, but the retinas of our patient were normal. One of the remaining 4 patients was diagnosed as having ACTH deficiency as was ours, but the diagnosis of the patient was myoclonus epilepsy associated with ragged red fibers (MERRF). The last 3 patients, who were diagnosed as having Boucher-Neuh?user syndrome, were similar to ours in terms of cerebellar ataxia but they were different in the presence of different hormone deficiencies and chorionretinopathy. Such an association of SCA3 and isolated ACTH deficiency as found in our patient has not been reported previously. The pathogenic mechanism of this association remains to be solved.     

Behavioral and developmental disorders among conduct disorder

The purpose of the present study was to clarify the percentage of children with conduct disorder (CD) who also have behavioral and developmental disorders. A survey of comorbidity observed in children with CD, was carried out on 33 subjects from a disciplinary facility for children. Female teachers as the mother were interviewed as regards the subjects' condition using the semistructured interview, and male teachers as the father were interviewed for their psychosocial problems. The subjects underwent the Wechsler Intelligence Scale for Children (WISC)-III and their conditions were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV). Of the 33 children, 27 were diagnosed as having CD. Of the 27 CD children, 18 (67%) were diagnosed as having attention deficit hyperactivity disorder (ADHD), and 19 (70%) had oppositional defiant feature (ODF). Eight children (30%) were diagnosed as having mental retardation and in seven children (26%), the verbal IQ was significantly lower than the performance IQ. Two (7%) were diagnosed as having pervasive developmental disorders (PDD). Of 27 children diagnosed with CD, 23 (85%) had some behavioral and developmental disorders. The classification of these behavioral and developmental disorders into the following three types appeared to be clinically useful: type 1, ADHD and ODF; type 2, low intelligence, especially low verbal intelligence; and type 3, PDD. To understand and treat children with CD, the accurate diagnosis of these underlying behavioral and developmental disorders is indispensable.     

Adult-type metachromatic leukodystrophy with compound heterozygous ARSA mutations: a case report and phenotypic comparison with a previously reported case

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A. MLD is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year-old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with MLD by genetic analysis, which revealed compound heterozygous ARSA missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that demonstrated frontal lobe dysfunction. These results indicate that the mutations have important implications for genotype-phenotype correlation in MLD.     

Atypical presentation and neuropathological studies in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency

A 6 1/2-month-old male offspring of consanguineous Egyptian parents was first seen because of fever, somnolence, vomiting, right focal motor seizures, right hemiparesis, elevated transaminase levels, hyperammonemia, and acidosis. A computed tomographic scan of the head suggested swelling of the left cerebral hemisphere, and an electroencephalogram indicated left frontotemporal abnormalities, but brain biopsy demonstrated diffuse white matter spongiosis and gliosis. Subsequently, urine organic acid analysis and enzyme assays were diagnostic of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.