Hematologic Manifestations in Primary Mitochondrial Diseases.

Primary mitochondrial disorders (PMDs) are known for their pleiotropic manifestations in humans, affecting almost any organ or system at any time. Hematologic manifestations, such as cytopenias and sideroblastic anemia, occur in 10% to 30% of patients with confirmed PMDs. These can be the initial presenting features or complications that develop over time. Surveillance for these manifestations allows for prompt identification and treatment. This article provides an overview of the pathophysiology underpinning the hematologic effects of mitochondrial dysfunction, discussing the 3 key roles of the mitochondria in hematopoiesis: providing energy for cell differentiation and function, synthesizing heme, and generating iron-sulfur clusters. Subsequently, the diagnosis and management of mitochondrial disorders are discussed, focusing on hematologic manifestations and the specific conditions commonly associated with them. Through this, we aimed to provide a concise point of reference for those considering a mitochondrial cause for a patient's hematologic abnormality, or for those considering a hematologic manifestation in a patient with known or suspected mitochondrial disease.

Developmental delay and non-phenylketonuria (PKU) hyperphenylalaninemia in DNAJC12 deficiency: Case and approach.

BACKGROUND: Hyperphenylalaninemia is a biomarker for several monogenic neurotransmitter disorders where the body cannot metabolise phenylalanine to tyrosine. Biallelic pathogenic variants in DNAJC12, co-chaperone of phenylalanine, tyrosine, and tryptophan hydroxylases, leads to hyperphenylalaninemia and biogenic amines deficiency. METHODS AND RESULTS: A male firstborn to non-consanguineous Sudanese parents had hyperphenylalaninemia 247 µmol/L [reference interval (RI) < 200 µmol/L] at newborn screening. Dried blood spot dihydropteridine reductase (DHPR) assay and urine pterins were normal. He had severe developmental delay and autism spectrum disorder without a notable movement disorder. A low phenylalanine diet was introduced at two years without any clinical improvements. Cerebrospinal fluid (CSF) neurotransmitters at five years demonstrated low homovanillic acid (HVA) 0.259 µmol/L (reference interval (RI) 0.345-0.716) and 5-hydroxyindoleaetic acid (5HIAA) levels 0.024 µmol/L (reference interval (RI) 0.100-0.245). Targeted neurotransmitter gene panel analysis identified a homozygous c.78 + 1del variant in DNAJC12. At six years, he was commenced on 5-hydroxytryptophan 20 mg daily, and his protein-restricted diet was liberalised, with continued good control of phenylalanine levels. Sapropterin dihydrochloride 7.2 mg/kg/day was added the following year with no observable clinical benefits. He remains globally delayed with severe autistic traits. CONCLUSIONS: Urine, CSF neurotransmitter studies, and genetic testing will differentiate between phenylketonuria, tetrahydrobiopterin or DNAJC12 deficiency, with the latter characterised by a clinical spectrum ranging from mild autistic features or hyperactivity to severe intellectual disability, dystonia, and movement disorder, normal DHPR, reduced CSF HIAA and HVA. DNAJC12 deficiency should be considered early in the differential workup of hyperphenylalaninemia identified from newborn screening, with its genotyping performed once deficiencies of phenylalanine hydroxylase (PAH) and tetrahydrobiopterin (BH4) have been biochemically or genetically excluded.

Mitochondrial iron-sulfur cluster biogenesis and neurological disorders.

Iron-sulfur clusters (ISCs) are highly conserved moieties embedded into numerous crucial proteins in almost all bacteria, plants and mammals. As such, ISC biosynthesis is critical to cellular function. The pathway was first characterized in bacteria by the late 1990s, and over the subsequent 20 years there has been increasing understanding of its components in humans. Defects in the ISC pathway are now associated with many different human disease states, such as Friedreich ataxia and ISCU myopathy. Whilst the disorders have variable clinical features, most involve neurological phenotypes. There are common biochemical signatures in most of these conditions, as a lack of ISCs causes deficiencies of target proteins including Complex I, II and III, aconitase and lipoic acid. This review focuses on the disorders of ISC biogenesis that have been described in the literature to-date. Key clinical, biochemical and neuroradiological features will be discussed, providing a reference point for clinicians diagnosing and managing these patients. Therapies are mostly supportive at this stage. However, the improved understanding of the pathophysiology of these conditions could pave the way for disease-modifying therapies in the near future.

Serum fibroblast growth factor 21 and growth differentiation factor 15: Two sensitive biomarkers in the diagnosis of mitochondrial disorders.

Mitochondrial disorders are often difficult to diagnose because of diverse clinical phenotypes. FGF-21 and GDF-15 are metabolic hormones and promising biomarkers for the diagnosis of these disorders. This study has systematically evaluated serum FGF-21 and GDF-15 levels by ELISA in a well-defined cohort of patients with definite mitochondrial disorders (n = 30), neuromuscular disease controls (n = 36) and healthy controls (n = 36) and aimed to ascertain their utility in the diagnosis of mitochondrial disorders. Both serum FGF-21 and GDF-15 were significantly elevated in patients with mitochondrial disorders, especially in those with muscle involvement. The levels were higher in patients with mitochondrial deletions (both single and multiple) and translation disorders compared to respiratory chain subunit or assembly factor defects.

Ethylmalonic encephalopathy ETHE1 p. D165H mutation alters the mitochondrial function in human skeletal muscle proteome.

Ethylmalonic encephalopathy (EE) is a rare autosomal recessive inborn error of metabolism. To study the molecular effects of ETHE1 p. D165H mutation, we employed mass spectrometry-based mitochondrial proteome and phosphoproteome profiling in the human skeletal muscle. Eighty-six differentially altered proteins were identified, of which thirty-seven mitochondrial proteins were differentially expressed, and most of the proteins (37%) were down-regulated in the OXPHOS complex-IV. Also, nine phosphopeptides that correspond to eight mitochondrial proteins were significantly affected in EE patient. These altered proteins recognized are involved in several pathways and molecular functions, predominantly in oxidoreductase activity. This is the first study that has integrated proteome and phosphoproteome of skeletal muscle and identified multiple proteins associated in the pathogenesis of EE.

Leukodystrophies and Genetic Leukoencephalopathies in Children Specified by Exome Sequencing in an Expanded Gene Panel.

The overlapping clinical and neuroimaging phenotypes of leukodystrophies pose a diagnostic challenge to both clinicians and researchers alike. Studies on the application of exome sequencing in the diagnosis of leukodystrophies are emerging. We used targeted gene panel sequencing of 6440 genes to investigate the genetic etiology in a cohort of 50 children with neuroimaging diagnosis of leukodystrophy/genetic leukoencephalopathy of unknown etiology. These 50 patients without a definite biochemical or genetic diagnosis were derived from a cohort of 88 patients seen during a 2.5-year period (2015 January-2017 June). Patients who had diagnosis by biochemical or biopsy confirmation (n = 17) and patients with incomplete data or lack of follow-up (n = 21) were excluded. Exome sequencing identified variants in 30 (60%) patients, which included pathogenic or likely pathogenic variants in 28 and variants of unknown significance in 2. Among the patients with pathogenic or likely pathogenic variants, classic leukodystrophies constituted 13 (26%) and genetic leukoencephalopathies 15 (30%). The clinical and magnetic resonance imaging (MRI) findings and genetic features of the identified disorders are discussed.