Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI: 10-Year follow up

Early initiation of enzyme replacement therapy (ERT) has demonstrated clinical benefit in patients with mucopolysaccharidosis type VI (MPS VI), a progressive, multisystem autosomal recessive lysosomal disorder caused by N-acetylgalactosamine-4-sulphatase (ASB) deficiency and the consequent accumulation of glycosaminoglycan. A previous case report highlighted that 3 years of ERT with recombinant human ASB (galsulfase) was well tolerated and effective in two Japanese siblings with MPS VI who initiated ERT at 5.6 years and 6 weeks of age, respectively. This report describes 10-year follow-up data from these two siblings who continued ERT with weekly infusions of galsulfase 1 mg/kg. Ten years of ERT was well tolerated, and the older sibling reached puberty. He had typical MPS VI phenotypic features, but exhibited significant improvement in shoulder range of motion and had largely unchanged hearing and cardiac function. His skeletal deformity remained unchanged. In contrast, in the younger sibling, typical symptoms of MPS VI, including progressive dysmorphic facial features, hepatosplenomegaly, and hearing impairment were largely absent. Her joint mobility was preserved, although skeletal deformity, including claw-hand deformity, was observed. Both siblings had progressive corneal clouding. The observations in these two patients suggest that early ERT initiated in newborns can be well tolerated and effective in preventing or slowing MPS VI disease progression, but is limited in terms of its effects on bone symptoms. For this, new approaches or bone-targeting treatments would be necessary

Clinical characteristics of epileptic seizures in a case of dihydropteridine reductase deficiency

We assessed the clinical characteristics and efficacy of neurotransmitters and levetiracetam in a patient with hyperphenylalaninemia due to dihydropteridine reductase (DHPR) deficiency who developed epileptic seizures. A boy with DHPR deficiency, who had been successfully treated with tetrahydrobiopterin (BH4), levodopa, and 5-hydroxytryptophan (5-HTP) since he was 2 months old, started having monthly episodes of blurred vision, loss of consciousness, and falls at the age of 12 years. He was taking BH4 510 mg/day, levodopa 670 mg/day, 5-HTP 670 mg/day, and entacapone 300 mg/day. We evaluated the seizure semiology, EEG findings, and efficacy of levodopa, 5-HTP, and levetiracetam (LEV). His seizures were comprised of an abrupt loss of awareness and eye deviation to the right. Interictal EEG showed slightly slow posterior-dominant rhythm in 7–8 Hz; intermittent, irregular slowing in the bilateral parieto-occipital region; and multiregional independent spikes in bilateral hemispheres. Ictal EEG showed a seizure pattern starting at the left temporal region. Brain MRI showed diffuse signal increase of deep white matter on T2-weighted and FLAIR images. Dosage increase of levodopa to 1340 mg/day, of 5-HTP to 1500 mg/day, or of both did not suppress seizures. Levetiracetam 2000 mg/day markedly reduced seizures without any adverse events. Patients with DHPR deficiency can develop epileptic seizures of partial onset which can be successfully and safely treated with LEV

Parkinsonism in Association with Dihydropteridine Reductase Deficiency

We report a 16-year-old man with disorders of tetrahydrobiopterin metabolism due to dihydropteridine reductase (DHPR) deficiency. He revealed moderate mental retardation, parkinsonism, and spastic paralysis with levodopa and 5-hydroxytryptophan (5-HTP) supplementation from the age of 2 months. Brain MRI showed high intensity areas in bilateral frontal and posterior deep white matter on fluid-attenuated inversion recovery (FLAIR). Coronal FLAIR image showed a high signal in bilateral pyramidal tracts. Single photon computed tomography (SPECT) imaging of the dopamine transporter was normal. This imaging indicates no dopaminergic cell loss. Our patient had no motor fluctuations or dyskinesias. Early diagnosis and replacement treatment might lead to a favorable outcome

Persistent urogenital sinus in siblings due to a maternal adrenal neoplasm: A case report

Introduction: The most prevalent cause of virilization in newborns is congenital adrenal hyperplasia. A very infrequent cause, on the other hand, is a virilizing maternal adrenal tumor. We present two 46XX siblings with virilization of the external genitalia due to androgen exposure secondary to a maternal androgen-producing tumor. Case presentation: Two female siblings born 8 years apart had ambiguous genitalia and persistent urogenital sinus (UGS) at birth. The older sister underwent a clitoroplasty and vaginoplasty at the age of 1 year. At the age of 11 years, she underwent an MRI that confirmed the presence of two ovaries, one uterus and one vagina. An additional vaginoplasty was done at the age of 17 years to dilate the vaginal orifice. She currently identifies as a female and is sexually active. The younger sister underwent a clitoroplasty and vaginoplasty at the age of 2 years. She underwent an MRI at the age of 16 years that confirmed the presence of two ovaries, one uterus and one vagina. She underwent vaginoplasty and urogenital sinus mobilization at the age of 17 years. When the patients were 16 and 8 years of age, the mother was diagnosed with an androgen-secreting left adrenal adenoma. At the time of the diagnosis the hormone levels were androstenedione 19 ng/ml (normal: 0.28–1.35), dehydroepiandrosterone-sulfate 2950 μg/dl (normal: 58–327), and testosterone 4.1 pg/ml (normal: 0.3–1.8). These findings explain the ambiguous genitalia of the female siblings. The mother underwent an uneventful complete resection of the tumor. Conclusion: In a case of female siblings with disorders of sex development of unknown origin, a maternal source of excess androgens must be ruled out. The type and timing of the genital reconstruction must be evaluated on a case-by-case basis and include the patient in the decision-making process

Generation of a human induced pluripotent stem cell line, BRCi001-A, derived from a patient with mucopolysaccharidosis type I

Mucopolysaccharidosis type I (MPS I) is a rare inherited metabolic disorder caused by defects in alpha-L-iduronidase (IDUA), a lysosomal protein encoded by IDUA gene. MPS I is a progressive multisystemic disorder with a wide range of symptoms, including skeletal abnormalities and cognitive impairment, and is characterized by a wide spectrum of severity levels caused by varied mutations in IDUA. A human iPSC line was established from an attenuated MPS I (Scheie syndrome) patient carrying an IDUA gene mutation (c.266G > A; p.R89Q). This disease-specific iPSC line will be useful for the research of MPS I

Genetic and pharmacological correction of aberrant dopamine synthesis using patient iPSCs with BH4 metabolism disorders.

患者由来iPS細胞とゲノム編集技術を用いて, BH4代謝病のドパミン合成異常の疾患モデル系構築に成功 : iPS細胞利用による代謝改善生理活性物質の同定と疾患再定義. 京都大学プレスリリース. 2016-10-28.Dopamine (DA) is a neurotransmitter in the brain, playing a central role in several disease conditions, including tetrahydrobiopterin (BH4) metabolism disorders and Parkinson's disease (PD). BH4 metabolism disorders present a variety of clinical manifestations including motor disturbance via altered DA metabolism, since BH4 is a cofactor for tyrosine hydroxylase (TH), a rate-limiting enzyme for DA synthesis. Genetically, BH4 metabolism disorders are, in an autosomal recessive pattern, caused by a variant in genes encoding enzymes for BH4 synthesis or recycling, including 6-pyruvoyltetrahydropterin synthase (PTPS) or dihydropteridine reductase (DHPR), respectively. Although BH4 metabolism disorders and its metabolisms have been studied, it is unclear how gene variants cause aberrant DA synthesis in patient neurons. Here, we generated induced pluripotent stem cells (iPSCs) from BH4 metabolism disorder patients with PTPS or DHPR variants, corrected the gene variant in the iPSCs using the CRISPR/Cas9 system, and differentiated the BH4 metabolism disorder patient- and isogenic control iPSCs into midbrain DA neurons. We found that by the gene correction, the BH4 amount, TH protein level and extracellular DA level were restored in DA neuronal culture using PTPS deficiency iPSCs. Furthermore, the pharmacological correction by BH4 precursor sepiapterin treatment also improved the phenotypes of PTPS deficiency. These results suggest that patient iPSCs with BH4 metabolism disorders provide an opportunity for screening substances for treating aberrant DA synthesis-related disorders