Nutrition 31 (2015) 1452–1455

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Effect of a 5-mo nutritional intervention on nutritional status and quality of life for patient with 3-hydroxyisobutyryl-coenzyme A hydrolase deficiency: A case report Chun-wei Li M.D. a, Kang Yu M.D. a, *, Yan Xu M.D. b, Xia-yuan Sun M.D. b, Rong-rong Li M.D. a, Fang Wang M.D. a a Department of Clinical Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China b Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 20 January 2015 Accepted 26 March 2015

3-Hydroxy-isobutyryl-coenzyme A (CoA) hydrolase (HBICH) deficiency is a rare cerebral organic aciduria caused by disturbance of valine catabolism that leads to the accumulation of toxic metabolites, methacrylyl-CoA. The major feature exhibited by a patient with HBICH deficiency includes multiple congenital malformations and abnormal neurologic findings. However, the pathophysiology of this disease remains unknown. The major treatment for HBICH deficiency involves a low-protein diet, especially restricting valine, supplemented with micronutrients and carnitine. To our knowledge, only four patients with HBICH deficiency have been reported. These patients were boys and presented with different clinical, biochemical, and genetic features than our patient. In this report, we described what was to our knowledge the first genetically confirmed girl with HBICH deficiency in China. A 5-mo nutritional intervention was given to the patient by a nutritional support team. On this regimen, the patient’s symptoms were alleviated and her quality of life was improved. Ó 2015 Elsevier Inc. All rights reserved.

Keywords: 3-Hydroxy-isobutyryl-CoA hydrolase Valine catabolism Nutritional intervention Valine-restrict regimen Nutritional support team

Introduction Deficiency of 3-hydroxy-isobutyryl-coenzyme A (CoA) hydrolase (HIBCH) is a rare cerebral organic aciduria caused by disturbance of valine catabolism that leads to the accumulation of toxic metabolites, methacrylyl-CoA (MC-CoA). HIBCH is a mitochondrial enzyme that catalyses the fifth step of valine catabolism, the conversion of 3-hydroxy-isobutyryl-CoA to 3-hydroxyisobutyrate [1]. The enzyme defect results in the accumulation of MC-CoA, a proximal metabolite in the valine degradation pathway, which can play a causative role. Activities of HIBCH in human liver are very high compared with that of branched chain a-keto acid dehydrogenase complex, suggesting an important role against the toxic effects of MC-CoA. MC-CoA can react with mitochondrial enzymes containing essential cysteine residues. The mitochondrial enzymes include pyruvate dehydrogenase complex (PDHC) and respiratory chain (RC) The authors declare no conflicts of interest. * Corresponding author. Tel.: þ86 10 6915 5550; fax: þ86 10 6525 3037. E-mail address: [email protected] (K. Yu). http://dx.doi.org/10.1016/j.nut.2015.03.012 0899-9007/Ó 2015 Elsevier Inc. All rights reserved.

enzymes [1]. Cysteine and cysteamine react with MC-CoA, and the conjugates accumulate in multiple organs, particularly the liver, kidney, and brain. Depletion of cysteine can lead to reduced activity of mitochondrial enzymes containing iron-sulfur (Fe-S) clusters (e.g., complexes I, II, and III and the Krebs cycle enzyme aconitase), since cysteine provides sulphide for Fe-S clusters [1]. Only four patients with HIBCH deficiency have been reported by retrieving PubMed and relevant cited papers. These patients were boys and presented with different clinical, biochemical, and genetic features than our patient. As far as we know, our report describes the first case of a genetically confirmed girl with HIBCH deficiency in China, who presented with combined defects of RC enzymes (complex V) and PDHC. The nutritional support team provided individualized nutritional intervention based on the results of nutritional screening and assessment.

Case report The index case was the first child of nonconsanguineous parents. She was full-term normal delivery, without neonatal

Table 1 Clinical and biochemical features of HIBCH deficiency Patient 2 [1]

Patient 3 [1]

Patient 4 [2]

Patient 5 [3]

Female 2.5 y Asophia Unrelated parents

Male Birth Dysmorphic features First cousin Egyptian parents

þþ No þ Persistent episodes of myotonia with pain after activity

Male Birth Poor feeding Distantly related parents; Younger þþ þþ þ Recurrent episodes of screaming, breath-holding, poor sleep, central apnea, visual impairment, microcephaly

Male 4 mo Head bobbing Unrelated parents

Dystonia Hypotonia Developmental regression Other clinical features

þþ þ þ Cerebellar ataxia-truncal ataxia, dysmetria, and intention tremor

NS þþ NS Facial dysmorphism, tetralogy of Fallot, multiple vertebral anomalies, agenesis of cingulate gyrus and corpus callosum

Venous blood lactate (A; p.G317

No Homozygous c.950 G>A; p.G317 E

I, IV Compound heterozygous c.365 A>G; p.Y122 C and IVS2-3 C>G; p.R27 fsX50

ND Homozygous c.219_220 insTTGAATAG; p.K73 fsX86

Hydroxy-C4-carnitine (G and exon5 C. 3837>A). Although her parents were nonconsanguineous, they exhibited gene exon mutation (paternal exon13, maternal exon 5). The analysis of blood organic acid showed significant deficiency of aspartic acid, methionine, arginine, glycine, ornithine, histidine, and serine. Her general practioner added baclofen and arginine, and her general condition improved. At 6.5 mo, the mild symptom was lower extremity stiffness with pain for w40 min, the serious symptom was bilateral lower extremity stiffness for w1 h with the contraction of waist muscle about for w30 min, even opisthotonos. Her symptom was associated with the time and degree of exercise. No K-F ring or abnormal abdominal appearance was found on physical examination. Blood biochemical examinations revealed hyperammonemia (Amon 46.0 mmol/L, reference range 11–32 mmol/L), hypoproteinemia (PA 189 mg/L, reference range 200–400 mg/L), and elevated creatine kinase (244 U/L, reference range 24–170 u/L). Cerebrospinal fluid routine, biochemically and lactate level (LA 1.59 mmol/L, reference range 1 h

Severe

2 3

4

5

Clinical and biochemical details of this patient and other patients with HIBCH deficiency previously reported in the literature [1–3] are summarized in Table 1. Nutritional screening, assessment, intervention, and monitoring are critical steps in nutritional diagnosis and treatment. Our team conducted nutritional screening and assessment for the patient on day 2 of admission. Her height and weight were 121 cm (P50–P75) and 19.6 kg (P50), respectively. Her skeletal muscle mass was 8.2 kg measured by bioelectrical impedance analysis (BIA). Although BIA cannot be used in children, we chose a way to observe the dynamic change of the patient’s skeletal cmuscle mass. Based on biochemical and metabolic abnormalities, our team decided to give the patient individualized nutritional intervention. We provided her with a special diet regimen composed of a low-valine diet and special formula enteral nutrition (EN). The diet contained adequate energy, appropriate protein-restricting valine, and micronutrients. The EN designed for methylmalonic acidemia or propionic aciduriaMaxamaind XM-2 came from Nutricia SHS International Company (Liverpool, United Kingdom) and contained a small amount of isoleucine. It was free of valine, methionine, and threonine. The energy intake of the regimen was 1600 to 1700 kcal/d according to energy calculation formula for under 12-y-old children/1000 þ age  70–100; total daily protein intake was 1 to 1.2 g/kg and daily valine intake was 700 to 1100 mg. We provided 50 g EN plus 200 mL cool boiled water once per day and other nutrients from oral food. The dose, proportion, and frequency of EN and food were revised according to weight, biochemical indexes, and intolerance caused by EN. Additionally, the patient was told to avoid food containing a large amount of valine, such as poultry, meat, eggs, and fish. To monitor the effects of nutritional intervention, our team formulated a scale that depended on symptom, episodes duration and degree of pain (Table 2). On this regimen, blood ammonia, the severity of symptoms and frequency of episodes, and prealbumin levels improved 1 mo after nutritional intervention. However, the patient’s weight and height did not change. It is possible that either the disease leads to growth retardation or her parents misunderstood the difference of raw weight and cooked weight of staple food, so the child’s energy consumption was inadequate. Based on her blood ammonia level, the patient gradually stopped taking arginine. At her second follow-up after 3 mo of nutrition intervention, the patient still presented intermittent episodes, although symptoms were alleviated. Her ammonia elevated to within normal range, but her prealbumin levels were slightly reduced. Moreover, her weight and height increased. Hence, we decided

C.-w. Li et al. / Nutrition 31 (2015) 1452–1455

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Table 3 Change of symptom, biochemical data, and development

Symptom

Duration of episodes

Degree of pain Score of symptom Exercise intensity Blood ammonia (mmol/L) Prealbumin (mg/L) Height (cm) Body weight (kg) *

Before intervention

First follow-up

Second follow-up

Third follow-up

Bilateral lower extremity stiffness Waist muscle contraction Opisthotonos Lower extremity stiffness w1 h Waist muscle contraction w30 min Opisthotonos state w10 min Severe 5 Low 49.7 162 121 19.6

Bilateral lower extremity stiffness Waist muscle contraction

Lower extremity stiffness Waist muscle contraction

*

Lower extremity stiffness w1 h Waist muscle contraction w20 min

Lower extremity stiffness w40 min Waist muscle contraction w5 min

*

Moderate 3 Low 10.0 209 121 19.6

Mild 2 Moderate 19.1 196 125 20

* 0 High 26.2 241 125 21.6

No episode.

to adjust her total daily protein intake from 1.2 to 1.5 g/kg and increase energy intake 200 kcal/d. At her third follow-up after 5 mo of nutritional intervention, no episodes were reported. All blood biochemical indexes were within normal range. Furthermore, her weight increased. Hence, we added egg or meat every day. The change of symptoms, biochemical data, and developmental status during the 5-mo nutritional intervention, is summarized in Table 3.

gastrointestinal tract [7–9]. Because the patient’s symptoms were associated with time and degree of physical activity, the degree of dystonia could not be quantified easily, and it was difficult to evaluate the effectiveness of the regimen. As a result, our team assessed the effectiveness of nutritional intervention and revised the regimen according to symptom scale, biochemical data, and growth.

Discussion

A regimen composed of a low-valine diet and a special EN formula can maintain metabolic homeostasis, relieve symptoms, postpone progression of the disease, and improve quality of life.

The nutritional support team, led by a dietitian, was composed of a dietitian, a physician, a pharmacist, and a nurse. The team discussed and provided an individualized nutritional intervention regimen according to symptoms, pathophysiology, metabolic condition, medical history, biochemical examination, and nutritional status. Pathophysiology There is no effective medication for HBICH deficiency other than palliative care. Therefore, nutritional intervention plays an essential role in maintaining metabolic homeostasis and postponing progression of the disease. The goal of nutritional intervention for the HBICH deficiency was to reduce toxic metabolites by restricting dietary valine to the proper level, thus allowing the patient to achieve and maintain plasma valine concentrations within normal ranges. However, there is no agreement on the normal range of plasma valine concentrations for patients with HIBCH deficiency. One study reported maintaining plasma valine concentrations at between 200 and 400 mmol/L for individuals with maple syrup urine disease to avoid metabolic instability [4]. Moreover, it has been recommended that children ages 4 to 7 y with valine metabolism disorder receive 700 to 1100 mg/d valine 0.6 to 1.2 g/Kg whole protein daily [5]. The treatment of the disease is challenging. Dietary protein must be prescribed to avoid overwhelming accumulation of the metabolite, but it is also important to provide enough highquality protein to prevent catabolism and to promote growth. Long-term strict diet control leads to reduced plasma valine concentrations, which may result in poor growth [6] and severe but reversible epithelial damage to skin, eyes, and the

Conclusion

Acknowledgment The authors acknowledge Xiao-dong Shi for her cooperation and support. References [1] Ferdinandusse S, Waterham HR, Heales SJR, Brown GK, Hargreaves LP, Taanman JW, et al. HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase. Orphanet J Rare Dis 2013;4:188. [2] Loupatty FJ, Clayton PT, Ruiter JP, Ofman R, Ijlst L, Brown GK, et al. Mutations in the gene encoding 3-hydroxyisobutyryl-CoA hydrolase results in progressive infantile neurodegeneration. Am J Hum Genet 2007;80:195–9. [3] Brown GK, Hunt SM, Scholem R, Fowler K, Grimes A, Mercer JF, et al. Betahydroxyisobutyryl coenzyme a deacylase deficiency: a defect in valine metabolism associated with physical malformations. Pediatrics 1982;70: 532–8. [4] Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, et al. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Mol Genet Metab 2014;112:210–7. [5] Bruce AB. Disorders of valine-isoleucine metabolism. In: Hoffmann NB, Clarke JL, editors. Physician’s guide to the treatment and follow-up of metabolic diseases. Berlin: Springer Publishing; 2006. p. 81–92. [6] Strauss KA, Morton DH. Branched-chain ketoacyl dehydrogenase deficiency: maple syrup disease. Curr Treat Options Neurol 2003;5:329–41. [7] Strauss KA, Wardley B, Robinson D, Hendrickson C, Rider NL, Puffenberger EG, et al. Classical maple syrup urine disease and brain development: principles of management and formula design. Mol Genet Metab 2010;99:333–45. [8] Koch SE, Packman S, Koch TK, Williams ML. Dermatitis in treated maple syrup urine disease. J Am Acad Dermatol 1993;28(Pt 2):289–92. [9] Tornqvist K, Tornqvist H. Corneal deepithelialization caused by acute deficiency of isoleucine during treatment of a patient with maple syrup urine disease. Acta Ophthalmol Scand Suppl 1996;219:48–9.