Johanna Uusimaa

Oulu University Hospital

Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Intere...

Background and objective: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. Methods: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, c...

HIDEA syndrome is caused by biallelic pathogenic variants in P4HTM. The phenotype is characterized by muscular and central hypotonia, hypoventilation including obstructive and central sleep apneas, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and an increased tendency to develop respiratory distress during pneumonia. Here, we...

Objective: To add to our knowledge of the clinical spectrum of patients with single large-scale mitochondrial DNA (mtDNA) deletion and childhood onset anemia. Methods: Retrospective collection of clinical data from medical records for patients, both living and deceased, with a single large-scale mtDNA deletion from seven mitochondrial disease cent...

Background Transcriptomic and proteomic profiling of human brain tissue is hindered by the availability of fresh samples from living patients. Postmortem samples usually represent the advanced disease stage of the patient. Furthermore, the postmortem interval can affect the transcriptomic and proteomic profiles. Therefore, fresh brain tissue sample...

The loss of NHL repeat containing 2 (Nhlrc2) leads to early embryonic lethality in mice, but the exact timing is currently unknown. In this study, we determined the time of lethality for Nhlrc2 knockout (KO), C57BL/6NCrl‐Nhlrc2tm1a(KOMP)Wtsi/Oulu, embryos and the in situ expression pattern of Nhlrc2 based on LacZ reporter gene expression during thi...

Aims: This study aimed to investigate associations between renal and extrarenal manifestations of mitochondrial diseases and their natural history as well as predictors of renal disease severity and overall disease outcome. The secondary aim was to generate a protocol of presymptomatic assessment and monitoring of renal function in patients with a...

Background Large-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset....

Objective Paediatric movement disorder patients can benefit from deep brain stimulation (DBS) treatment and it should be offered in a timely manner. In this paper we describe our experience establishing a DBS service for paediatric patients. Methods We set out to establish a paediatric DBS (pDBS) procedure in Oulu University Hospital in northern F...

The modification of genes in animal models has evidently and comprehensively improved our knowledge on proteins and signaling pathways in human physiology and pathology. In this review, we discuss almost 40 monogenic rare diseases that are enriched in the Finnish population and defined as the Finnish disease heritage (FDH). We will highlight how ge...

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency due to the homozygous PCK1 variant has recently been associated with childhood-onset hypoglycemia with a recognizable pattern of abnormal urine organic acids. In this study 21 children and three adult patients with genetically confirmed PEPCK-C deficiency were diagnosed during the yea...

Background Transcriptomic and proteomic profiling of human brain tissue is hindered by availability of fresh samples from living patients. Postmortem samples usually represent the advanced disease stage of the patient. Furthermore, the postmortem interval affects the observed transcriptomic and proteomic profiles. Therefore, access to fresh brain t...

Background: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied five Finnish and two Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction and immunodeficiency. Objective: To further characterize phenotypes and disease mechanisms associated with loss of DI...

Background FINCA disease is a pediatric cerebropulmonary disease caused by variants in the NHL repeat-containing 2 ( NHLRC2 ) gene. Neurological symptoms are among the first manifestations of FINCA disease, but the consequences of NHLRC2 deficiency in the central nervous system are currently unexplored. Methods The orthologous mouse gene is essent...

Objective: To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. Methods: Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the avai...

Purpose To compare the value of serum biomarkers, FGF21 and GDF15 with histological analysis of muscle in the diagnosis of mitochondrial disease. Methods We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme labelled immunosorbent assay (ELISA). Clinical data was...

TATA‐box binding protein associated factor, RNA polymerase I subunit C (TAF1C ) is a component of selectivity factor 1 belonging to RNA polymerase I (Pol I) transcription machinery. We report two unrelated patients with homozygous TAF1C missense variants and an early‐onset neurological phenotype with severe global developmental delay. Clinical feat...

Background Variants in POLG are one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. Metho...

Background : Mitochondrial diabetes is primarily caused by β-cell failure, a cell type whose unique properties are important in pathogenesis. Methods : By reducing glucose, we induced energetic stress in two rodent β-cell models to assess effects on cellular function. Results : Culturing rat insulin-secreting INS-1 cells in low glucose conditions c...

Purpose: A new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane pro...

Purpose: Next-generation sequencing (NGS) has made genetic testing of patients with epileptic encephalopathies easier - novel variants are discovered and new phenotypes described. Variants in the same gene - even the same variant - can cause different types of epilepsy and neurodevelopmental disorders. Our aim was to identify the genetic causes of...

Objective Previous studies have suggested that heterozygous variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma (POLG1) increase the risk for liver injury for patients on valproate (VPA) therapy. We assessed the prevalence of these common variants and seven other pathogenic mutations in POLG1 and determined the occurrence of VPA‐in...

The development of tissue fibrosis is complex and at the present time, not fully understood. Fibrosis, neurodegeneration and cerebral angiomatosis (FINCA disease) have been described in patients with mutations in NHL repeat -containing protein 2 (NHLRC2). However, the molecular functions of NHLRC2 are uncharacterized. Herein, we identified putative...

NHLRC2 (NHL repeat-containing protein 2) is an essential protein. Mutations of NHLRC2, including Asp148Tyr, have been recently associated with a novel FINCA disease (fibrosis, neurodegeneration, cerebral angiomatosis), which is fatal in early childhood. To gain insight into the mechanisms of action of this essential protein, we determined the cryst...

Internal symmetry of the NHLRC2 β-propeller. (A) Structural superimposition of the six blades. Strand A and D are indicated. Each blade fragment starts from the cup residues (top) and the first three β-strands (A–C) superimpose well. The backbone RMSD between all six blades ~0.8 Å. (B) Structure-based alignment of the six blades. Blade numbers are...

SAXS analysis of the full-length NHLRC2. (A) Raw SAXS data collected for concentration series (5 mg/ml in green, 2.5 mg/ml in blue and 1.25 mg/ml in purple) overlaid with theoretical scattering curve calculated from NHLRC2 (9–572) crystal structure using CRYSOL (in red). Guinier regions for each dataset are shown in the inset. (B) Rg and I(0)/c plo...

Superimposition of NHLRC2. Trx-like domain (A) and β-propeller domain (B) with structural homologs identified by DALI search. Structural homologs are indicated with the corresponding PDB code. DipZ from M. tuberculosis (2HYX; [17]), DsbF from M. tuberculosis (1ZZO; [[38]), DsbE from P. aeruginosa (3KH7; [39]), thiol-disulfide exchange protein TlpA...

Comparison of NHLRC2 with SOQ1. (A) Sequence alignment. Conserved residues are marked in red color. CCINC motif is indicated by arrowheads and Asp-148 by asterisk. (B) Conserved residues are indicated on NHLRC2 (9–572) structure and shown in stick representation in red color. (TIF)

Objective Epilepsy is common in individuals with mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma. Early recognition and aggressive seizure management are crucial for patient survival. Disruption of the blood‐brain barrier (BBB) is implicated in various neurological disorders including epilepsy. T...

Alexander disease (AxD) is a genetic leukodystrophy caused by GFAP mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, wi...

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary...

Background Leigh syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder. While some genetic defects are associated with well-described phenotypes, phenotype-genotype correlations in Leigh syndrome are not fully explored. Objective We aimed to identify phenotype-genotype correlations in Leigh syndrome in a large cohort of...

Mitochondrial ribosomal 12S subunit gene ( MTRNR1 ) is a hot spot for hearing loss mutations. Mutations such as m.1555A>G, m.1494C>T and m.1095C>T, cause sensitivity to aminoglycosides. Aminoglycoside treatment induces permanent hearing loss or deafness in the carriers and should therefore be avoided. The prevalence of these sensitivity mutations v...

Background : Mitochondrial diabetes is primarily caused by β-cell failure, a cell type whose unique properties are important in pathogenesis. Methods : By reducing glucose, we induced energetic stress in two rodent β-cell models to assess effects on cellular function. Results : Culturing rat insulin-secreting INS-1 cells in low glucose conditions c...

Objective: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and SAMD9L mutations. Methods: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured intervie...

Mitochondria produce adenosine triphosphate (ATP) for energy requirements via the mitochondrial oxidative phosphorylation (OXPHOS) system. One of the hallmarks of cancer is the energy shift towards glycolysis. Low OXPHOS activity and increased glycolysis are associated with aggressive types of cancer. Mitochondria have their own genome (mtDNA) enco...

Background Methionine synthase deficiency is a rare inborn error of intracellular cobalamin metabolism caused by mutations in the MTR (5-methyltetrahydrofolate-homocysteine S-methyltransferase) gene, resulting in megaloblastic anemia and neurologic symptoms. Methods and Results We describe for the first time a homozygous MTR gene c.3518C > T (p.P11...

Mutations in GLE1, RNA export mediator (GLE1) gene have previously been shown to cause motor neuron diseases such as Lethal congenital contracture syndrome 1 (LCCS1) and Lethal arthrogryposis with anterior horn cell disease (LAAHD), including arthrogryposis, fetal akinesis and motor neuron loss as common clinical features. The homozygous FinMajor m...

Background Mitochondrial cytochrome c oxidase 2, MT-CO2, encodes one of the three subunits, which form the catalytic core of cytochrome c oxidase (COX), complex IV. Mutations in MT-CO2 are rare and the associated phenotypes are variable including nonsyndromic and syndromic forms of mitochondrial diseases. Case presentationWe describe a 30-year-old...

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting both fatty acid and amino acid oxidation. It can manifest at any age, but riboflavin-responsiveness has mainly been described in less severely affected patients. We describe an infant with severe MADD presenting with profound hypotonia and hepatomegaly....

Background: Mitochondrial diabetes is primarily caused by β-cell failure, but there are gaps in our understanding of pathogenesis. Methods: By reducing glucose, we induced energetic stress in two rodent β-cell models to assess effects on cellular function. Results: Culturing rat insulin-secreting INS-1 cells in low glucose conditions caused a rapid...

Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located o...

Background Mitochondrial diseases present with variable multi-organ symptoms. Common disease-causing mutations in mitochondrial DNA (mtDNA) are regularly screened in diagnostic work-up, but novel mutations may remain unnoticed. Methods Patients (N = 66) with a clinical suspicion of mitochondrial disease were screened for their mtDNA coding region...

Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was...

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic diseases characterized by impaired hematopoiesis and progression to acute myeloid leukemia (AML). Although rare, several monogenic causes of familial MDS/AML have recently been molecularly defined. We studied two families with variable manifestation of cytopenia, MDS wi...

Objective: To validate new mitochondrial myopathy serum biomarkers for diagnostic use. Methods: We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease a...

Due to the relative rarity of mitochondrial diseases, generating reference ranges is problematic in evaluation of respiratory chain activities particularly in pediatric cases. We determined the sample distribution of respiratory chain enzyme activities in skeletal muscle biopsies collected from pediatric patients suspected of neuromuscular disorder...

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two famil...

Background: The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. Pa...

Purpose: To investigate the association of mutations in the mitochondrial DNA (mtDNA) or nuclear candidate genes with mitochondrial disease-related ophthalmic manifestations (nystagmus, ptosis, ophthalmoplegia, optic neuropathy and retinopathy) in children. Methods: A retrospective cohort of children (n = 98) was identified from the medical reco...

To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions. Muscle DNA samples from patients presenting with undefined encephalomyopathies or myopathies were analysed for mtDNA content b...

Objective To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases, in order to estimate the role of mtDNA rearrangements in pathogenesis of these diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions. Methods Muscle DNA samples...

Background and aims: Patients with mutations in the POLG1 gene encoding the mitochondrial DNA polymerase gamma have an increased risk of valproate-induced liver failure. POLG1 mutations are common among populations and these patients often suffer from intractable seizures. The role of liver transplantation in the treatment of patients with mitochon...

Leigh syndrome is a progressive neurodegenerative disorder, associated with primary or secondary dysfunction of the mitochondrial oxidative phosphorylation. Despite the fact that Leigh syndrome is the most common phenotype of mitochondrial disorders in children, longitudinal natural history data is missing. This study was undertaken to assess the p...

The sirtuins (SIRTs; SIRT1-7) are a family of NAD(+)-dependent enzymes that dynamically regulate cellular physiology. Apart from SIRT1, the functions and regulatory mechanisms of the SIRTs are poorly defined. We explored regulation of the SIRT family by 2 energy metabolism-controlling factors: peroxisome proliferator-activated receptor γ coactivato...

Background: Leigh syndrome (LS) is an early-onset, progressive neurodegenerative disorder, associated with defects involving mitochondrial oxidative phosphorylation. It is the most common distinct mitochondrial disease phenotype in children. Objectives: To study the phenotypic and genotypic spectrum of patients with LS, characterise the clinical co...

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are severe autosomal recessive disorders associated with decreased mtDNA copy number in clinically affected tissues. The hepatocerebral form (mtDNA depletion in liver and brain) has been associated with mutations in the POLG, PEO1 (Twinkle), DGUOK and MPV17 genes, the latter encoding a mitochondri...

Purpose To assess the frequency and clinical features of childhood-onset intractable epilepsy caused by the most common mutations in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma. Methods Children presenting with nonsyndromic intractable epilepsy of unknown etiology but without documented liver dysfunctio...