A Case With the Infantile Type of Glycerol Kinase Deficiency

A male infant with the infantile type of glycerol kinase deficiency is described. At six years of age, he showed proximal dominant muscle atrophy and weakness, addisonian pigmentation and mental retardation. Laboratory investigations revealed muscular dystrophy, adrenal insufficiency and glycerol kinase deficiency. He has a small deletion in a band (Xp21) of the X chromosome. The clinical, biochemical and genetic findings in this patient are reported.     

Progressive high frequency hearing loss: An additional feature in the syndrome of congenital adrenal hypoplasia and gonadotrophin deficiency

In an earlier report, we found that X-linked congenital adrenal hypoplasia may be associated with gonadotrophin deficiency. This combination has since been confirmed by many others. At the last examination, our patients were 22.4, 19.9 and 17.5 years old. They were doing well on replacement therapy with hydrocortisone, fluorohydrocortisone, and long-acting testosterone, but in all of them, a progressive hearing loss had appeared, starting at high freqencies at about 14 years of age. The loss progressed with age to lower frequencies, and the oldest patient had some remaining hearing capacity at 125–500 Hz only with a perceptive hearing loss of –95 dB at frequencies above 500 Hz. It is concluded that patients with this syndrome should be examined for hearing loss. X-linked adrenal hypoplasia may also be associated with glycerol kinase deficiency and myopathy. A molecular XP-deletion has suggested a locus for hypogonadotrophic hypogonadism distal to the glycerol kinase and adrenal hypoplasia loci. The observations in our patients suggest that the locus for at least this type of X-linked deafness may be in the same area.     

Glycerol kinase deficiency inhibits glycerol utilization in phosphoglyceride and triacylglycerol biosynthesis

Glycerol 3-phosphate is an initial metabolite in the biosynthesis of phosphoglycerides and triacylglycerols. Both glycerol and glucose are precursors of glycerol 3-phosphate. Cultured skin fibroblasts from patients with glycerol kinase deficiency utilized glucose, but not glycerol in the biosynthesis of phosphoglycerides and triacylglycerols. Phosphoglyceride and triacylglycerol biosynthesis in glycerol kinase deficiency fibroblasts is not diminished by the inability to use glycerol as a precursor of glycerol 3-phosphate.     

Infantile glycerol kinase deficiency— a condition requiring prompt identification

Infantile glycerol kinase deficiency (GKD) is an X-linked genetic disease characterized clinically by adrenal insufficiency and muscular dystrophy. The enzyme defect leads to increased levels of glycerol in blood and urine, which can be used for diagnosis. Without recognition of this condition, the chances for life-saving steroid treatment and for genetic counselling are missed. We report clinical, endocrinological, biochemical, and morphological findings in two non-related boys. One of them died in early infancy. The other is thriving at the age of 2 years although he is suffering from a myopathy not distinguishable from Duchenne muscular dystrophy. We discuss when to suspect and how to confirm the diagnosis of infantile GKD, and under what precautions the condition is detectable by commonly used screening procedures for inborn errors of metabolism.     

Phenotypic features of patients with congenital adrenal hypoplasia and glycerol kinase deficiency

Two unrelated boys with congenital adrenal hypoplasia and glycerol kinase deficiency were found to have similar features, including characteristic facies, testicular abnormalities, short stature, psychomotor retardation, and muscular dystrophy. The resemblance of these boys to other patients described in the literature suggests that a distinct phenotypic syndrome occurs in children with congenital adrenal hypoplasia and glycerol kinase deficiency.     

Intravenous glycerol therapy should not be used in patients with unrecognized fructose-1,6-bisphosphatase deficiency

BACKGROUND: In Asian countries, glycerol solution that contains fructose (5%) is often used for management of brain edema. However, glycerol and fructose may cause severe hypoglycemia and metabolic acidosis in patients with fructose-1,6-bisphosphatase (FBPase) deficiency, even under stable conditions. The aim of the present study was to determine whether glycerol solution was used for brain edema during acute metabolic decompensation of hypoglycemia and metabolic acidosis in patients with unrecognized FBPase deficiency in Japan and to examine a long-term prognosis of the patients who had this kind of severe metabolic decompensation with or without glycerol therapy. METHODS: A retrospective study of 20 children with FBPase deficiency was conducted, based on their medical records. RESULTS: Six of the 20 children were given glycerol solution for the presence or possibility of brain edema during acute metabolic decompensation of hypoglycemia and metabolic acidosis; two of the six patients administered with glycerol were given dialysis. In four patients treated with glycerol alone without dialysis, two had no brain edema before glycerol administration but it developed later after the administration. These four patients treated with glycerol alone died or developed severe neurological complications. Fourteen patients who were not treated with glycerol solution had no brain edema and showed good prognosis. CONCLUSIONS: Glycerol solution, which contains fructose in Asian countries including Japan, should not be used as an osmotic agent for treatment of brain edema in patients who have hypoglycemia and retention-type metabolic acidosis, until FBPase deficiency is ruled out by measuring blood concentration of lactate.     

Duchenne muscular dystrophy, glycerol kinase deficiency, and adrenal insufficiency associated with Xp21 interstitial deletion

We report an interstitial deletion in the short arm of the X chromosome in a 6-year-old boy with Duchenne muscular dystrophy, glycerol kinase deficiency, adrenal insufficiency, intermittent hypoglycemia, spasticity, psychomotor retardation, and growth delay. His mother also has this deletion in an X chromosome. From our findings, we propose that the human glycerol kinase locus and the human X-linked adrenal hypoplasia locus are in the Xp21 band.     

Folinic acid therapy in treatment of dihydropteridine reductase deficiency

We gave folinic acid to three siblings, and to a fourth child, who have or had dihydropteridine reductase (DHPR) deficiency. The youngest began folinic acid therapy in addition to neurotransmitter precursors and a phenylalanine-restricted diet at age 2 months, and at 2 years of age has near normal development without evidence of neurologic impairment. His older brother began similar treatment at 5 1/2 months of age, when early neurologic findings were evident. At age 6 years his mental retardation and neurologic impairment are less severe than reported in most patients with DHPR deficiency. Little improvement occurred in their sister, who first received treatment at 2 years of age, when she already had severe neurologic impairment. An unrelated boy with profound neurologic impairment showed subtle signs of improvement after he began treatment with folinic acid alone at age 9 years. These results provide evidence that folinic acid is important in the treatment of DHPR deficiency and, if begun early in infancy, may prevent irreversible neurologic damage. The mechanism of folinic acid action in DHPR deficiency may be to increase indirectly the synthesis of 5-methyltetrahydrofolate.     

Glycerol kinase deficiency: follow-up during 20 years, genetics, biochemistry and prognosis

AIM: To follow two children with isolated glycerol kinase deficiency (GKD) with severe symptoms into adulthood. METHODS: The patients were followed during approximately 20 y and interviewed about symptoms, diet and physical activity. Fasting provocations, bicycle ergometer tests, dietary registrations, enzyme and mutation analysis were performed by standard protocols. RESULTS: The activity of glycerol kinase (GK) in fibroblasts was <10% of reference. One case had a deletion of exon 17, the other a mutation in exon 7 of the GK gene (601 A-->G). Both mothers were heterozygotes. Two maternal male cousins in one of the families were hemizygotes without symptoms. Tests performed in childhood documented pronounced sensitivity to fasting and physical exercise, whereas such tests at 23 and 31 y of age were essentially normal but with pronounced ketonaemia. After puberty, the boys had no hypoglycaemic symptoms and now report no problems with their condition; thus, their phenotype has changed over time. CONCLUSION: The greater importance of glycerol as a gluconeogenetic substrate in children than in adults may explain the episodes in young patients with GKD, often elicited by catabolic stress. With meals at frequent intervals, access to glucose and avoidance of strenuous sports, the prognosis is good for a normal adult life of a young child with isolated GKD and symptoms of hypoglycaemia.     

Gonadotropin Deficiency as a Significant Association of Complex Glycerol Kinase Deficiency: A Case Report with Cytogenetic and Molecular-Genetic Studies

A 6-year-old Japanese male patient with complex glycerol kinase deficiency (CGKD) is described. In addition to glycerol kinase deficiency, congenital adrenal hypoplasia, Duchenne muscular dystrophy, mental retardation and short stature, gonadotropin deficiency (GTD) was confirmed. The continuous stimulation of LHRH recovered the increment of serum LH and FSH values. Cytogenetic and molecular-genetic studies revealed a deletion in the Xp21 region which may involve many genes. Although a few cases of CGKD associated with GTD and/or cryptorchidism have been described, the cause of GTD has not been mentioned in the literature. The simultaneous occurrence of CGKD and GTD in these patients including ours may not be coincidental, but suggests the existence of a certain gene in the Xp21 region which may affect the development of hypothalamic LHRH secretory function. Therefore detailed and repeated evaluations of gonadotropin secretion are necessary in patients with CGKD.     

Complex glycerol kinase deficiency: An X-linked disorder associated with adrenal hypoplasia congenita

Complex glycerol kinase deficiency (GKD) results from the contiguous deletion on Xp21 of all or part of the gene for glycerol kinase together with that for adrenal hypoplasia congenita (AHC) and/or Duchenne muscular dystrophy (DMD). The authors present the case of a newborn whose initial issues were refractory hypoglycaemia along with hyponatremia and hyperkalemia. He also had low serum cortisol levels and raised urinary excretion of glycerol and required steroid supplementation. His creatinine phosphokinase (CPK) levels were normal. Molecular studies revealed a contiguous Xp21 deletion. Therapy in such cases must be prompt and includes correction of hypoglycaemia and dyselectrolytemia, a low fat diet and steroid replacement.     

反复纳差伴皮肤色素沉着2月余

2月龄男性,新生儿期起病,存在肾上腺皮质功能减退、肝功能损害、肌酶显著增高、高脂血症、电解质紊乱等多系统损害,结合微阵列比较基因组杂交技术发现的X染色体短臂(Xp21.3-p21.1)8.7 Mb致病性拷贝缺失,确诊为复合型甘油激酶缺乏症(cGKD)。予氢化可的松替代和大剂量辅酶Q10联合左卡尼汀治疗,并随访4年。治疗1周患儿皮质醇水平即恢复正常,但肌酸肌酶、甘油三脂及转氨酶进行性升高,伴智力发育落后及肌力减退。cGKD又称Xp21邻近基因缺失综合征,症状包括甘油激酶缺乏所致的高甘油三脂血症以及先天性肾上腺发育不良(AHC)、杜氏肌营养不良(DMD)、智力发育迟缓(MR)等症候群。对于以先天性肾上腺皮质功能不全为表现的患儿,应注意监测血肌酸激酶及甘油三脂水平,必要时行基因检测以免误诊。     

Congenital adrenal hypoplasia and glycerol kinase deficiency

An unusual case of salt-wasting in a male infant is reported. The cause was a small X-chromosomal deletion within Xp21 resulting in the syndrome of congenital adrenal hypoplasia with glycerol kinase deficiency. This syndrome can readily be diagnosed by routine biochemical tests.     

Congenital Adrenal Hypoplasia and Glycerol Kinase Deficiency

ABSTRACT. An unusual case of salt-wasting id a male infant is reported. The cause was a small X-chromosomal deletion within Xp21 resulting in the syndrome of congenital adrenal hypoplasia with glycerol kinase deficiency. This syndrome can readily be diagnosed by routine biochemical tests.     

Long-term survival in severe combined immune deficiency: the role of persistent maternal engraftment

Two siblings with severe combined immune deficiency, one with maternal engraftment and detectable immunologic functions who was alive at the age of 8 years are presented. Both patients had the same JAK3 gene mutation, suggesting that maternal engraftment may result in immune competence leading to long-term survival in patients with severe combined immune deficiency.     

Commentary

A girl with cystic fibrosis who developed a neurological syndrome probably secondary to vitamin E deficiency at the age of 10 years is described. The severity of the deficiency and the early development of neurological features probably result from reduced intraluminal bile salt concentrations in addition to the pancreatic insufficiency.     

Cleft palate and gonadotrophin deficiency.

A boy who had previously had a cleft lip and palate repaired and bilateral orchiopexies presented at 16 years of age with delayed puberty. Isolated gonadotrophin deficiency and testicular hyporesponsiveness to human chorionic gonadotrophin were found. The possibility of bilateral cryptorchidism due to gonadotrophin deficiency should be considered in boys with either cleft lip or palate, or both.     

Meningococcal conjugate vaccines policy update: booster dose recommendations

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention and the American Academy of Pediatrics approved updated recommendations for the use of quadravalent (serogroups A, C, W-135, and Y) meningococcal conjugate vaccines (Menactra [Sanofi Pasteur, Swiftwater, PA] and Menveo [Novartis, Basel, Switzerland]) in adolescents and in people at persistent high risk of meningococcal disease. The recommendations supplement previous Advisory Committee on Immunization Practices and American Academy of Pediatrics recommendations for meningococcal vaccinations. Data were reviewed pertaining to immunogenicity in high-risk groups, bactericidal antibody persistence after immunization, current epidemiology of meningococcal disease, meningococcal conjugate vaccine effectiveness, and cost-effectiveness of different strategies for vaccination of adolescents. This review prompted the following recommendations: (1) adolescents should be routinely immunized at 11 through 12 years of age and given a booster dose at 16 years of age; (2) adolescents who received their first dose at age 13 through 15 years should receive a booster at age 16 through 18 years or up to 5 years after their first dose; (3) adolescents who receive their first dose of meningococcal conjugate vaccine at or after 16 years of age do not need a booster dose; (4) a 2-dose primary series should be administered 2 months apart for those who are at increased risk of invasive meningococcal disease because of persistent complement component (eg, C5-C9, properdin, factor H, or factor D) deficiency (9 months through 54 years of age) or functional or anatomic asplenia (2-54 years of age) and for adolescents with HIV infection; and (5) a booster dose should be given 3 years after the primary series if the primary 2-dose series was given from 2 through 6 years of age and every 5 years for persons whose 2-dose primary series or booster dose was given at 7 years of age or older who are at risk of invasive meningococcal disease because of persistent component (eg, C5-C9, properdin, factor H, or factor D) deficiency or functional or anatomic asplenia.     

The role of plasma ferritin determination in screening for iron deficiency. Apropos of a study in 2 groups of children of different socioeconomic background

A study of 72 children, aged between 6 and 24 months who came from socio-economic background has shown: plasma ferritin levels decrease gradually between 3 weeks and 6 months of age. Between 6 months and two years, levels reach a plateau but the values are lower than those of adults. The mean ferritin level is lower at any given age in children with iron deficiency but plasma ferritin levels may be in the normal range although there is obvious iron deficiency. By contrast the saturation of siderophillin can be used to determine inadequate supplies of iron to the marrow. The frequency of iron dificiency in infants under 1 year was similar in the two socio-economic groups. However between 1 and 2 years no iron deficiency was detected in the children under regular supervision but all the infants who were socially disadvantaged became iron-deficient demonstrating the need for regular iron supplements.     

Late-onset ornithine transcarbamylase deficiency in male patients

We report on 21 male patients who presented after 28 days of age with ornithine transcarbamylase (OTC) deficiency, which we define as late-onset OTC deficiency. These patients appeared normal at birth, but irritability, vomiting, and lethargy, which were often episodic, later developed. The age at presentation ranged from 2 months to 44 years. Biochemical testing revealed hyperammonemia, hyperglutaminemia, hypocitrullinemia, increased urinary orotate excretion, and decreased liver OTC activity measured in vitro, which ranged from 0% to 15% of normal. Male patients who were older at presentation had a somewhat different pattern of presenting symptoms and were more likely to die. These data illustrate the phenotypic variability of OTC deficiency. Unexplained episodes of repetitive or protracted vomiting in association with progressive alterations in behavior or neurologic findings should suggest the diagnosis of a urea cycle defect (or another symptomatic inborn error of metabolism), regardless of the age or medical history of the patient.