Inherited Metabolic Disorders Involving the Nervous System

유지숙,Jeesuk Yu The Korea Society of Inherited Metabolic Disease 2023 대한유전성대사질환학회지 Vol.23 No.2

Inherited metabolic disorders (IMD) are a group of disorders caused by defects in specific biochemical pathways. Up to 85% of IMD display predominantly neurological manifestations by affecting neurodevelopment or causing neurodegeneration. These neurometabolic disorders present with a variety of neurological and non-neurological manifestations. Early diagnosis of IMD is important because some disorders can be treated or improved with specific treatment if detected early. For prompt diagnosis and treatment, it is important to suspect IMD by being familiar with the clinical characteristics, biochemical abnormalities, and characteristic neuroimaging patterns that appear in IMD. Genetic testing, including next-generation sequencing, is also important in diagnosing IMD. During the follow-up of patients with IMD, it is necessary to conduct regular physical and neurological examinations in addition to disease-specific management.

Skeletal Manifestations of Inborn Errors of Metabolism: A Comprehensive Retrospect

조성윤,Sung Yoon Cho The Korea Society of Inherited Metabolic Disease 2023 대한유전성대사질환학회지 Vol.23 No.1

Inborn errors of metabolism encompass a wide variety of disorders, frequently affecting bone. This review presents a comprehensive retrospect on the primary involvement of bone in inborn errors of metabolism. Primary involvement of bone in inborn errors of metabolism includes entities that primarily affect the bone marrow, mineral component or cartilage. These include lysosomal storage disorders, hypophosphatasia, and hereditary hypophosphatemic rickets. In this review, we discuss the primary involvement of bone in inborn errors of metabolism (hypophosphatasia, X-linked hypophosphatemic rickets, Gaucher disease, and mucopolysaccharidoses) along with the therapeutic agents used in clinical settings, diagnostic strategies, and general management. With the development of disease-specific targeted therapies and supportive care, more number of patients with these disorders live longer and survive into adulthood. Moreover, skeletal symptoms have become a more prominent feature of these disorders. This makes the awareness of these skeletal symptoms more important.

Defects in Ketone Body Metabolism and Pregnancy

Fukao, Toshiyuki The Korea Society of Inherited Metabolic Disease 2018 대한유전성대사질환학회지 Vol.18 No.3

Pregnancy and delivery pose a high risk of developing metabolic decompensation in women with defects of ketone body metabolism. In this review, the available reported cases in pregnancy are summarized. It is very important to properly manage women with defects of ketone body metabolism during pregnancy, especially nausea and vomiting in the first trimester of pregnancy, and during labor and delivery. Pregnant women with deficiencies of HMG-CoA lyase or succinyl-CoA:3-ketoacid CoA transferase (SCOT) often experience metabolic decompensations with nausea and vomiting of pregnancy, often requiring hospitalization. For successful delivery and to reduce stresses, vaginal delivery with epidural anesthesia or elective cesarean delivery with epidural or spinal anesthesia are recommended for women with HMG-CoA lyase and SCOT deficiency. In beta-ketothiolase deficiency, four pregnancies in three patients had favorable outcomes without severe metabolic problems.

A Case of Pseudodeficiency in a Potential Late Onset Pompe Disease Carrier, with Double Dual Variant, Each in cis Formation

김승호,김구련,장영표,이동환,Seung Ho, Kim,Goo Lyeon, Kim,Young Pyo, Chang,Dong Hwan, Lee The Korea Society of Inherited Metabolic Disease 2022 대한유전성대사질환학회지 Vol.22 No.2

Pompe disease (PD) is an autosomal recessive genetic disorder caused by a deficiency of the lysosomal enzyme acid α-glucosidase (GAA). It is easy to hastily diagnose as patients if they have two pathogenic variants. Clinical pathologists misdiagnosed our infant and her mother as PD. Here, we report a case of pseudodeficiency in a potential late-onset Pompe disease (LOPD) carrier with a double dual variant, each in cis formation in a 3-month infant. The person who has two pathogenic variants was diagnosed as a carrier, not a patient. It was first reported in Korea. The patient had: two likely pathogenic heterozygous mutations on exon #4: c.752C>T (p.Ser251Leu), c.761C>T (p.Ser254Leu), and a heterozygous mutation on exon #12: c.1726G>A (p.Gly576Ser), also with a heterozygous mutation on exon #15: c.2065G>A (p.Glu689Lys). By presenting this case we emphasize the possibility of cis formation of genes which may cause pseudodeficiency, and potential LOPD carrier form. Hereby we suggest that thorough evaluation of GAA gene is essential among whom initially diagnosed as PD.

18-year Follow-up of Extended Newborn Screening for Metabolic and Endocrine Disorders

송웅주,이선호,전영미,김숙자,장미영,Song, Wung Joo,Lee, Sunho,Jeon, Young Mi,Kim, Sook Za,Jang, Mea Young The Korea Society of Inherited Metabolic Disease 2018 대한유전성대사질환학회지 Vol.18 No.2

Purpose: To follow up Korean patients with metabolic and endocrine disorders ascertained by Korea Genetics Research Center, and assess the long-term effectiveness of extended newborn screening program in Korea. Methods: From January 2000 to December 2017, tandem mass spectrometry and fluoroimmunoassay were employed in extended newborn screening (NBS). The NBS program obtained dried blood spots from 283,626 babies, 48 hours after birth, and screened for galactosemia, congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), and 50 preventable inborn errors of amino acid, fatty acid, and organic acid metabolism. Results: 28 cases of amino acid disorders, 75 cases of organic acid disorders, 27 cases of fatty acid disorders, 51 cases of urea cycle disorders, 127 cases of CH, 14 cases of CAH, and 15 cases of galactosemia were ascertained through NBS and subsequent confirmatory laboratory tests. Patients with amino acid metabolic disorders, galactosemia, CH, or CAH were more likely to have a better long-term outcome if detected early. Early management of MSUD led to much better outcome in over 90%. Despite early intervention, 32% of other organic acidemia cases still resulted in developmental delay and neurological problems. Fatty acid disorders showed varied results; those with EMA and MCAD had a good outcome, but those with VLCAD had serious neurological problems and considerably higher mortality. 75% with UCD experienced serious neurological complications and higher mortality. Conclusion: The nation-wide NBS program must be accompanied by comprehensive long-term management and physician and family education of inborn errors of metabolism for a better outcome.

Somatic Cell Analysis and Cobalamin Responsiveness Study in Ten Korean Patients with Methylmalonic Aciduria

임한혁,송웅주,김구환,김유미,장미영,길홍량,김숙자,Lim, Han Hyuk,Song, Wung Joo,Kim, Gu-Hwan,Watkins, David,Rosenblatt, David S.,Kim, Yoo-Mi,Chang, Mea Young,Kil, Hong Ryang,Kim, Sook Za The Korea Society of Inherited Metabolic Disease 2019 대한유전성대사질환학회지 Vol.19 No.1

Purpose: Isolated methylmalonic acidemia (MMA) is an autosomal recessive inherited disorder of propionate metabolism. There are two subtypes of MMUT gene defects. $Mut^0$ represents complete loss of methylmalonyl-CoA mutase (MCM) activity while mut- is associated with residual MCM activity, which can be stimulated by hydroxocobalamin (OHCbl) supplementation. The objective of this study is to investigate cobalamin responsiveness and mutations present in Korean MMA population. Methods: We evaluated 10 MMA patients using somatic cell complementation analysis on their fibroblasts to measure MCM activity and vitamin B12 responsiveness for the optimal treatment. MMUT gene was sequenced to identify the MMA mutations. Results: For all patients, the incorporation of $[^{14}C]-propionate$ was low, and there was no response to OHCbl. The incorporation of $[^{14}C]-methyltetrahydrofolate$ and $[^{57}Co]-CNCbl$ fell within the normal range. There was adequate synthesis of methylcobalamin while the synthesis of adenosylcobalamin was low. The complementation analysis showed all patients were $mut^0$. The sequence analysis identified 12 different MMUT mutations, including 2 novel mutations, p.Gln267Ter and p.Ile697Phe, were identified. All the patients in this study had neonatal onset of symptoms, belonged to $mut^0$ complementation class, and as a result, showed no cobalamin responsiveness. Conclusion: No Korean MMA patient showed cobalamin responsiveness.

Cardiac Manifestations of Inborn Error of Metabolism in Pediatric Patients

오지영,Oh, Jiyoung The Korea Society of Inherited Metabolic Disease 2021 대한유전성대사질환학회지 Vol.21 No.1

Among the various etiologies of cardiomyopathy, inborn errors of metabolism (IEM) is one of the underlying causes, especially in the pediatric population. The accurate identification of the IEM of cardiomyopathy may lead to better prognosis through disease-specific management. Therefore, clinicians should always keep in mind the possibility that IEM may be one of the underlying etiologies of cardiomyopathy, and carry out multi-systematic clinical approach to diagnosis of IEM. This review covers the pathophysiology, clinical presentations, typical laboratory findings, diagnosis, and proper treatment of each type of IEM-induced cardiomyopathy in pediatric patients to gain a deeper understanding of this subject.

A Case of Urologic Manifestation of IARS2-associated Leigh Syndrome

이현주,나지훈,이영목,Hyunjoo Lee,Ji-Hoon Na,Young-Mock Lee The Korea Society of Inherited Metabolic Disease 2023 대한유전성대사질환학회지 Vol.23 No.1

Leigh syndrome is a rare progressive neurodegenerative mitochondrial disorder with clinical and genetic heterogeneity. Recently, balletic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes from Leigh and West syndrome to a rare syndrome CAGSSS characterized by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia syndrome (OMIM#616007). We describe a child with Korean Leigh syndrome with urologic manifestations resulting from a compound heterozygote mutation in IARS2. A 5-year-old girl visited the emergency room with a complaint of abdominal pain accompanied by abdominal distension. Abdominal-pelvic CT showed a markedly distended urinary bladder without definite obstructive lesions. She was diagnosed with neurogenic bladder dysfunction based on a urodynamic study. She had global delayed development due to neurologic regression after 6 months of age and a history of bilateral cataract surgery at the age of 2 years. Her brain magnetic resonance imaging showed symmetrically increased signal intensities in the bilateral putamen and caudate nuclei with diffuse cerebral atrophy. No gene variants were identified through whole-mitochondrial genome analysis. Whole exome sequencing was performed for diagnosis, and compound heterozygous pathogenic variants were identified in IARS2: c.2446C>T (p. Arg816Ter) and c.2450G>A (p. Arg817His). To the best of our knowledge, this is the first case report of bladder dysfunction manifestation in a patient with IARS2-related Leigh syndrome. Thus, it broadens the clinical and genetic spectrum of IARS2-associated diseases.

Evaluation of the Congenital Hypothyroidism for Newborn Screening Program in Korea: A 14-year Retrospective Cohort Study

윤혜란,안선현,이향자,Yoon, Hye-Ran,Ahn, Sunhyun,Lee, Hyangja The Korea Society of Inherited Metabolic Disease 2019 대한유전성대사질환학회지 Vol.19 No.1

목적: 선천성 갑상선기능저하증(Congenital hypothyroidism, CH)은 전세계적으로 출생아 3,000-4,000명 당 1명의 빈도로 발생하는 신생아기에 가장 흔한 내분비질환이다. 본 연구는 1991년부터 2004년까지 남한의 선천성 갑상선기능저하증 발생률의 빈도 및 현재까지 적용되어온 광범위한 신생아 선별검사의 검사방법과 결과를 재평가하기 위해 수행되었다. 방법: 서울 지역에 위치하지만 전국적인 지사를 운영하고 있는 검사기관 서울의과학 연구소(SCL)에서는 서울 외 6개 광역시(부산, 인천, 대구, 대전, 광주, 울산)와 9개도(경기, 강원, 충북, 충남, 전북, 전남, 경북, 경남, 제주)로 한국을 15개 지역으로 분류하였다. 15개 지역으로부터 신생아의 채혈지를 수집하여 서울본원에서 수집하여, TSH 및 유리 T4를 ELISA 검사법으로 신생아선별검사를 수행하였다. SCL 데이터 및 복지부에 보고된 전국적인 양성자수를 검토하였다. 선천성갑상선기능저하증에 대한 신생아선별 검사법의 cut-off 치는 신생아 갑상선자극호르몬(TSH) 측정을 위해서는 20 mIU/L를 유리 T4의 검사를 위해서는 0.8 ng/dL 이하를 사용하였다. TSH 및 유리 T4 ELISA 분석에 기초한 선천성 갑상선기능저하증에 대해 1차 선별검사에서 선천성 갑상선기능저하증 양성은 신생아 671,805명 중 신생아 159명에서 발견되었으며, 이의 발병빈도는 4,225명 중 1명으로 추정되었다 결과: TSH 분석에서 cut-off 20 mIU/ L를 사용했을 때 민감도, 특이도 및 양성 측도(PPV)는 각각 100.0%, 99.7% 및 10.8%였다. 유리 T4 분석을 위해 0.8 ng/dL cut-off를 사용했을 때 민감도, 특이도 및 양성 예측도는 각각 100.0%, 98.5% 및 3.9%였다. 결론: NBS를 통해 얻은 CH의 발병빈도는 2004년 이전에 해외의 여러 국가에서 보고 된 발병빈도와 비교할 만큼 유사하였다.

Clinical and Biochemical Diagnosis in Children with Leigh Syndrome

이선호,전미나,이현주,박대영,김세훈,이영목,Lee, Sun Ho,Jeon, Mina,Lee, Hyun Joo,Park, Dae Young,Kim, Se Hoon,Lee, Young-Mock The Korea Society of Inherited Metabolic Disease 2015 대한유전성대사질환학회지 Vol.15 No.2

Purpose: Deficits of the respiratory chain are reported to be the major cause of Leigh syndrome is said to be the underlying causes. The need for biochemical diagnosis to draw more accurate diagnosis or prognosis to support treatments is rapidly increasing. This study tried to analyze the aspects of clinical characteristics and biochemical diagnosis of mitochondrial respiratory chain complex (MRC) defect in Leigh syndrome, using methods of biochemical enzyme assay. Methods: We included total number of 47 patients who satisfied the clinical criteria of Leigh syndrome and confirmed by biochemical diagnosis. All those patients went through muscle biopsy to perform biochemical enzyme assay to analyze MRC enzyme in order to find the underlying cause of Leigh syndrome. Results: MRC I defect was seen in 23 (48.9%) cases taking the first place and MRC IV defect in 15 (31.9%) following it. There were 9 (19.2%) cases of combined MRC defect. Combined cases of type I and IV were detected in 7 (14.9%) patients while type I and V in 2 (4.3%). The onset age of symptom was less than 1 year old in 28 (59.6%). The most common early symptom, observed in 23 (48.9%), was delayed development, but there were other various neurological symptoms observed as well. In regard with the disease progression, 35 (74.5%) patients showed slowly progressive course, the one that progressed continuously but slowly over 2 years of period. As for Maximum motor development, 22 (46.8%) were bed-ridden state, most of them suffering serious delayed development. Patients showed various symptoms with different organs involved, though neuromuscular involvement was most prominent. Delayed development was seen in all cases. Multifocal lesion in brain MRI study was seen in 36 (76.6 %) cases, taking a greater percentage than 11 (23.4%) cases with single lesion. In MR spectroscopy study, the characteristic lactate peak of mitochondrial disease was identified in 20 (42.6%) patients. Conclusions: Further analysis of clinical and biochemical diagnosis on more extended group of patients with Leigh syndrome will enable us to improve diagnostic precision and to understand the natural course of mitochondrial disease.