Ulrike Löbel

Brain iron quantification by MRI in mitochondrial membrane protein-associated neurodegeneration under iron-chelating therapy

Therapeutic trials for Neurodegeneration with Brain Iron Accumulation have aimed at a reduction of cerebral iron content. A 13‐year‐old girl with mitochondrial membrane protein‐associated neurodegeneration treated with an iron‐chelating agent was monitored by R2 relaxometry, R2* relaxometry, and quantitative susceptibility mapping to estimate the brain iron content. The highly increased brain iron content slowly decreased in the substantia nigra but remained stable for globus pallidus. The estimated iron content was higher by R2* compared to R2 and quantitative susceptibility mapping, a finding not previously observed in the brain of healthy volunteers. A hypothesis explaining this discrepancy is offered.

Fatal neurological side-effects with necrosis of spinal cord following nelarabine treatment in a child with relapsed T-cell acute lymphoblastic leukemia.

The article by Kawakami et al. demonstrated severe and irreversible neurological side effects in patients who received nelarabine prior to haploidentical stem cell transplantation [1]. We report an 11-year-old boy with a second combined bone marrow (BM) and central nervous system (CNS) relapse of his T cell acute lymphoblastic leukemia (T-;ALL) who suffered severe and fatal neurological sideeffects after one cycle of nelarabine treatment. Histopathologic examinations revealed severe necrotic changes in the nervous system corresponding to alterations in the MRI. At admission, the boy was in a good general condition without neurological deficits. Chemotherapy according to the recommendation by Commander et al. [2] including cyclophosphamide, etoposide, nelarabine, and one dose of intrathecal cytarabine, MTX, and prednisolone was started. BY day 5 of chemotherapy strong muscle pain in the limbs developed and two days later the boy suffered from a tonic-clonic seizure. Focal and generalized seizures reappeared over the next days. By day 12 of chemotherapy, the patient developed a Guillain–Barr e-like syndrome with hyperreflexia of both arms and hyporeflexia of both legs. Within the next eight days the patient lost sensitivity and reflexes of the lower limbs, developed painful dysesthesia of the arms and lost motor control. After a severe aspiration and cardio-pulmonary reanimation he was transferred to the intensive-care unit, requiring mechanical ventilation. Visual, auditory, and somatosensory evoked potentials were not detectable. By day 20 of chemotherapy, complete remission in the BM and CNS was observed. However, because of the severe neurological symptoms, chemotherapy was stopped. The patient died in a blast crisis eleven weeks after start of chemotherapy without recovery of the neurological symptoms. Longitudinal MRI at days 6 through 74 after initiation of nelarabine treatment showed progressive T2-hyperintense lesions of the spinal cord, including the medial lemniscus and eventually involving its whole cross-sectional diameter. In addition, T2 signal changes of several cranial nerves were observed which were characterized by restricted water diffusion, suggesting cytotoxic edema (Fig. 1). Investigation of post-mortem samples of the nervous system revealed macrophage invasion, gliosis and tissue sponginess in the basal ganglia, thalamus, mammillary bodies, and occipital white matter. Alterations were more pronounced in the fiber tracts of the brain stem and the spinal cord was completely necrotic. Anterior spinal nerve roots showed advanced demyelination while the posterior roots appeared intact. Peripheral nerves exhibited segmental demyelination. Electron microscopy of brain tissue demonstrated macrophages loaded with myelin debris and whole degenerating myelinated axons (Fig. 2). Severe and even fatal neurological toxicities have been described after nelarabine therapy in several patients [1,3]. However, to our knowledge neuropathological changes like in the present case were not even detected in preclinical studies in primates suffering from nelarabine associated neurotoxicity [4]. Other causes of neurotoxicity can be excluded since the patient never received spinal irradiation, cranial irradiation dated back more than one year and no infection occurred after nelarabine treatment [5,6]. The patient received a single dose of intrathecal MTX, which may cause neurotoxicity. However, a single dose makes MTX as sole cause unlikely. In summary, our observations confirm the reported neurotoxicity observed by Kawakami et al.

Early-onset leukoencephalopathy due to a homozygous missense mutation in the DARS2 gene.

Mutations in the DARS2 gene are known to cause leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), a rare autosomal recessive neurological disorder. It was originally described as juvenile-onset slowly progressive ataxia and spasticity, but recent reports suggest a broader clinical spectrum. Most patients were found to carry compound heterozygous DARS2 mutations, and only very few patients with homozygous mutations have been described so far. We present here an 8-month-old boy carrying a homozygous missense mutation in DARS2 who clinically showed severe neurological deterioration after a respiratory tract infection, followed by an almost complete remission of symptoms. This report further extends the knowledge about the clinical and molecular genetic spectrum of LBSL.

LYRM7 - associated complex III deficiency: A clinical, molecular genetic, MR tomographic, and biochemical study

LYRM7 is involved in the last steps of mitochondrial complex III assembly where it acts as a chaperone for the Rieske iron‑sulfur (Fe-S) protein in the mitochondrial matrix. Using exome sequencing, we identified homozygosity for a splice site destroying 4 base pair deletion in LYRM7 in a child with recurrent lactic acidotic crises and distinct early-onset leukencephalopathy. Sanger sequencing showed variant segregation in similarly affected family members. Functional analyses revealed a reduced amount of the Rieske Fe-S protein, which was restored after re-expression of LYRM7. Our data provide further evidence for the importance of LYRM7 for mitochondrial function and emphasize the importance of whole exome sequencing in the diagnosis of rare mitochondrial diseases.

Unexplained loss of vision in a child: consider bilateral primary optic nerve sheath meningioma.

A 4-year-old girl gradually lost her vision to become practically blind at the age of 10 years. Examinations at several medical centers had been unable to establish an etiology. Traditional investigation using cerebral magnetic resonance imaging (MRI) initially showed normal results; however, later on it showed progressive atrophy of both optical nerves without recognizable cause. Subsequently, MRI including adequate orbital sequences, contrast-enhanced sequences, and fat suppression demonstrated bilateral primary optic nerve sheath meningioma, a rare but treatable tumor of childhood. The patient underwent neurosurgery and to date retains minimal vision. Adequate neuroradiological investigation of unexplained optic atrophy is advocated.

MRI demyelination pattern and clinical course in a child with cerebral X-linked adrenoleukodystrophy (X-ALD):

The clinical spectrum in boys with X-linked adrenoleukodystrophy (X-ALD) ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. In the individual case, the disease course still remains unpredictable. Research findings suggest an important role of brain magnetic resonance imaging (MRI) lesion patterns as prognostic markers for X-ALD. Hence, familiarity with imaging features of childhood X-ALD in combination with clinical manifestation is required in order to stratify affected patients for therapy. We report on MRI findings and clinical course of cerebral X-ALD in a young boy with a rare subtype of white matter demyelination.

Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits

Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G>A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A>C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case. Both patients presented similarly in early childhood with global developmental delay, raised CSF lactate and abnormalities on cranial MRI. Sanger sequencing of familial samples confirmed the segregation of bi-allelic GFM2 variants with disease, while investigations into steady-state mitochondrial protein levels revealed respiratory chain subunit defects and loss of mtEFG2 protein in muscle. These data demonstrate the effects of defective mtEFG2 function, caused by previously unreported variants, confirming pathogenicity and expanding the clinical phenotypes associated with GFM2 variants.