DNACJ12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant.

In addition to tetrahydrobiopterin deficiencies and phenylalanine hydroxylase deficiency (phenylketonuria) due to PAH variants, the deficiency of the co-chaperone protein DNAJC12 was identified in 2017 as a novel cause of inherited hyperphenylalaninemia, revealing the genetic etiology in previously unresolved cases. In this study, we aimed to investigate DNAJC12 deficiency in non-tetrahydrobiopterin-deficient persistent hyperphenylalaninemia cases without biallelic PAH variants in a single pediatric metabolic center. It was determined retrospectively that 471 patients with non-tetrahydrobiopterin deficiency-hyperphenylalaninemia had undergone PAH gene sequencing and 451 patients had biallelic variants in PAH. DNAJC12 sequencing was performed in the remaining 20 patients, identifying a previously reported homozygous splice-site variant (c.158-2A > T) in one patient with axial hypotonia and developmental delay, and a novel, homozygous c.404del (p.Arg135Lysfs*21) frameshift variant in an asymptomatic patient. In segregation analysis, the asymptomatic patient's both parents were also found to be homozygous for this variant and hyperphenylalaninemic. The parents may have had academic difficulties but intellectual disability could not be confirmed due to lack of cooperation. The symptomatic patient significantly benefited from treatment with sapropterin dihydrochloride and neurotransmitter precursors. DNAJC12 deficiency might be responsible for approximately 10% or more of cases with unexplained hyperphenylalaninemia. The phenotypic spectrum is broad, ranging from early infantile hypotonia to incidental diagnosis in adulthood. Similar to tetrahydrobiopterin deficiencies, early diagnosis and treatment with sapropterin dihydrochloride and neurotransmitter precursors can be beneficial, supporting the analysis of DNACJ12 gene in patients with unexplained hyperphenylalaninemia.

Correction to: DNAJC12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant.

A Correction to this paper has been published: https://doi.org/10.1007/s11011-021-00759-8.

Hereditary Dopamine Transporter Deficiency Syndrome: Challenges in Diagnosis and Treatment.

Hereditary dopamine transporter deficiency syndrome (DTDS) is a neurotransmitter disorder caused by a defect in the neuronal uptake of dopamine. To date, 20 patients are reported in the literature, and we present 2 additional patients with DTDS harboring novel homozygous SLC6A3 gene mutations. Patient A is an 8-month-old male with neonatal-onset hypotonia, who developed orolingual dyskinetic movements and oculogyric crises after 4 months of age, with evolution to status dystonicus episodes. Patient B is a 4-year-old male who also had hypotonia since birth, with additional severe limb contractions and oculogyric crises after the age of 3 months, with a misdiagnosis of epileptic encephalopathy. Both patients had consanguineous parents and similar cerebrospinal fluid (CSF) neurotransmitter profiles with elevated homovanillic acid and increased the ratio of homovanillic acid to 5-hydroxyindoleacetic acid. Diagnostic delay is 4 months, and 3 years 9 months, respectively. Treatment response to levodopa is poor. Early infantile-onset progressive dystonia with oculogyric crises, hypotonia, developmental delay, and CSF neurotransmitter profile led to a diagnosis of DTDS in these two patients. Management of hyperkinetic movement disorder, status dystonicus, and feeding difficulties are challenging. Detailed phenotyping of individual patients along with treatment response should provide insight into dopamine homeostasis.

Imaging liver nodules in tyrosinemia type-1: A retrospective review of 16 cases in a tertiary pediatric hospital.

OBJECTIVE: To describe the liver imaging findings of Hereditary tyrosinemia type-1 (HT1) patients. MATERIALS AND METHODS: We report 16 patients (8 Female and 8 Male) with HT-1. Their demographic features, imaging findings and alpha feto protein (AFP) levels were recorded. Imaging features on CT and MR were evaluated for the following characteristics: contour of the liver and liver nodules. Liver nodules were categorized as; regenerative, dysplastic, fatty and malignant nodules (HCC). RESULTS: Thirteen (81%) patients had multiple liver nodules (>20) on imaging studies. Five patients (31%) had regenerative nodules, six (38%) had dysplastic nodules and ten (63%) had fatty nodules. Dysplastic nodules were encountered in two patients with HCC and in four patients without a tumor. Four patients (25%) had HCC nodule on imaging studies. Those four patients had biopsy and all of them had HCC nodule on histopathology. In the follow-up period, in one patient fatty nodules had increased in size, in one patient regenerative nodules had disappeared and in one patient dysplastic nodules had disappeared. CONCLUSIONS: Multiple fatty nodules can be seen in HT1 patients and in some patients, the regenerative and dysplastic nodules can disappear during the follow-up period.

Evaluation of spinal involvement in children with mucopolysaccharidosis VI: the role of MRI.

OBJECTIVE: To evaluate spinal MRI features of mucopolysaccharidosis (MPS) VI and to assess the correlation with clinical findings. METHODS: We retrospectively evaluated spinal MRI scans and clinical findings at the time of imaging in 14 patients (8 male, 6 female) with MPS VI. Craniometric measurements were performed and the images were assessed for bony anomalies, spinal stenosis and spinal cord compression. The degree of cervical cord compression was scored and correlated with neurological examination findings at the time of imaging. Vertebral alignment, structural changes in spinal ligaments and intervertebral discs were also assessed. RESULTS: All patients had cervical stenosis due to bony stenosis and thickened retrodental tissue (median: 6.05 mm, range 3.3-8 mm). Retrodental tissue thickness was found to increase with age (p = 0.042). Compressive myelopathy was detected at upper cervical level in 11 (79%) and lower thoracic level in 2 patients (14%). Significant inverse correlation was found between cervical myelopathy scores and neurological strength scores. The most common bony changes were hypo/dysplastic odontoid; cervical platyspondyly with anterior inferior beaking; thoracic posterior end plate depressions and lumbar posterior scalloping. Kyphosis due to retrolisthesis of the beaked lumbar vertebrae and acute sacrococcygeal angulations were other remarkable findings. CONCLUSION: MRI is an essential component in evaluation of spinal involvement in MPS VI, and scanning of the entire spine is recommended to rule out thoracic cord compression. Advances in knowledge: This study provides a detailed description of spinal MRI findings in MPS VI and underlines the role of MRI in management of cord compression.

Cognitive and behavioral impairment in mild hyperphenylalaninemia.

Evinç SG, Pektas E, Foto-Özdemir D, Yildiz Y, Karaboncuk Y, Bilginer-Gürbüz B, Dursun A, Tokatli A, Coskun T, Öktem F, Sivri HS. Cognitive and behavioral impairment in mild hyperphenylalaninemia. Turk J Pediatr 2018; 60: 617-624. As elevated phenylalanine (Phe) is detrimental to brain functions, determining a safe upper limit of blood Phe is important for initiation of treatment plans and setting Phe targets in hyperphenlalaninemic patients. It is accepted that Phe levels below 360 µmol/L does not impair brain function and hence does not require treatment. Therefore, we aimed to compare cognitive functions and attention-related problems among healthy children and untreated patients with hyperphenylalaninemia (HPA). This study included 41 hyperphenylalaninemic patients (`all HPA group`) aged 6-16 years with untreated blood Phe between 240 and 600 µmol/L and 29 healthy controls. `All HPA group` was further divided into 2 subgroups according to their lifetime median blood Phe levels as `Phe 360-600 µmol/L` and `Phe 240-360 µmol/L` groups. Wechsler Intelligence Scale for Children-IV (WISC-IV), Conners` Continuous Performance Test (CPT), Strength and Difficulties Questionnaire (SDQ) and Schedule for Affective Disorders and Schizophrenia for School-Age Children: Present and Lifetime Version (K-SADS-PL) were performed as a comprehensive neurocognitive, attention and behavioral assessment. The study illustrated that `all HPA` patients had significantly lower scores on all WISC-IV indexes compared to controls, except for Working Memory. Both `Phe 360-600 µmol/L` and `Phe 240-360 µmol/L` subgroups had lower Full Scale intelligence quotient (IQ) and Verbal Comprehension scores compared to controls. `All HPA` patients also had longer reaction times and more peer problems than controls, indicating attention deficits and behavioral problems. Since the results demonstrated that children with untreated Phe levels between 240-360 µmol/L are at higher risk for cognitive and attention-related problems, lowering the `safe` upper Phe level should be considered.