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Purpose To describe an efficient and effective multiplex screening strategy for sulfatide degradation disorders and mucolipidosis type II/III (MLII/III) using 3 mL of urine. Methods Glycosaminoglycans were analyzed by liquid chromatography-tandem mass spectrometry. Matrix assisted laser desorption/ionization-time of flight tandem mass spectrometry was used to identify free oligosaccharides and identify 22 ceramide trihexosides and 23 sulfatides, which are integrated by 670 calculated ratios. Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu ) was used for post-analytical interpretation of the complex metabolite profile and to aid in the differential diagnosis of abnormal results. Results Multiplex analysis was performed on 25 sulfatiduria case samples and compiled with retrospective data from an additional 15 cases revealing unique patterns of biomarkers for each disorder of sulfatide degradation (MLD, MSD, and Saposin B deficiency) and for MLII/III, thus allowing the formulation of a novel algorithm for the biochemical diagnosis of these disorders. Conclusions Comprehensive and integrated urine screening could be very effective in the initial workup of patients suspected of having a lysosomal disorder as it covers disorders of sulfatide degradation and narrows down the differential diagnosis in patients with elevated glycosaminoglycans.

Introduction There is limited understanding of relationships between genotype, phenotype and other conditions contributing to health in neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) identified through newborn screening. Methods Retrospective analysis of comprehensive data from a cohort of 221 newborn-screened subjects identified as affected with MCADD in the Inborn Errors of Metabolism – Information System (IBEM-IS), a long term follow-up database of the Inborn Errors of Metabolism Collaborative, was performed. Results The average age at notification of first newborn screen results to primary care or metabolic providers was 7.45 days. The average octanoylcarnitine (C8) value on first newborn screen was 11.2 μmol/L (median 8.6, range 0.36–43.91). A higher C8 level correlated with an earlier first subspecialty visit. Subjects with low birth weight had significantly lower C8 values. Significantly higher C8 values were found in symptomatic newborns, in newborns with abnormal lab testing in addition to newborn screening and/or diagnostic tests, and in subjects homozygous for the c.985A > G ACADM gene mutation or compound heterozygous for the c.985A > G mutation and deletions or other known highly deleterious mutations. Subjects with neonatal symptoms, or neonatal abnormal labs, or neonatal triggers were more likely to have at least one copy of the severe c.985A > G ACADM gene mutation. C8 and genotype category were significant predictors of the likelihood of having neonatal symptoms. Neonates with select triggers were more likely to have symptoms and laboratory abnormalities. Conclusions This collaborative study is the first in the United States to describe health associations of a large cohort of newborn-screened neonates identified as affected with MCADD. The IBEM-IS has utility as a platform to better understand the characteristics of individuals with newborn-screened conditions and their follow-up interactions with the health system.

Leigh syndrome is a mitochondrial disease caused by mutations in different genes, including ATP6A for which no known therapy is available. We report a case of adult-onset Leigh syndrome with response to immunotherapy. A twenty year-old woman with baseline learning difficulties was admitted with progressive behavioral changes, diplopia, headaches, bladder incontinence, and incoordination. Brain MRI and PET scan showed T2 hyperintensity and increased uptake in bilateral basal ganglia, respectively. Autoimmune encephalitis was suspected and she received plasmapheresis with clinical improvement. She was readmitted 4 weeks later with dysphagia and aspiration pneumonia. Plasmapheresis was repeated with resolution of her symptoms. Given the multisystem involvement and suggestive MRI changes, genetic testing was done, revealing a homoplasmic T9176C ATPase 6 gene mtDNA mutation. Monthly IVIG provided clinical improvement with worsening when infusions were delayed. Leigh syndrome secondary to mtDNA T9176C mutations could have an autoimmune mechanism that responds to immunotherapy.

Past murine studies of phenylketonuria (PKU) have documented significant effects on cerebellum at both the gross and cellular levels. The profile of neurocognitive and motor difficulties associated with early-treated PKU (ETPKU) is also consistent with potential cerebellar involvement. Previous neuroanatomical studies of cerebellum in patients with PKU, however, have yielded mixed results. The objective of the present study was to further examine potential differences in cerebellar morphometry between individuals with and without ETPKU. To this end, we analyzed high resolution T1-weighted MR images from a sample of 20 individuals with ETPKU and an age-matched comparison group of 20 healthy individuals without PKU. Measurements of whole brain volume, whole cerebellum volume, cerebellar gray matter volume, and cerebellar white matter volume were collected by means of semiautomatic volumetric analysis. Data analysis revealed no significant group differences in whole brain volume, whole cerebellar volume, or cerebellar white matter volume. A significant reduction in cerebellar gray matter volume, however, was observed for the ETPKU group compared to the non-PKU comparison group. These findings expand on previous animal work suggesting that cerebellar gray matter is impacted by PKU. It is also consistent with the hypothesis that the cognitive difficulties experienced by individuals with ETPKU may be related to disruptions in gray matter. Additional studies are needed to fully elucidate the timing and extent of the impact of ETPKU on cerebellum and the associated neurocognitive consequences., Highlights • Past animal and human work suggests cerebellum may be impacted by PKU. • Significant reduction in cerebellar gray matter volume observed for ETPKU. • Cerebellar white matter volumes similar for ETPKU and non-PKU participants.

Phenylketonuria (PKU) is a rare genetic condition characterized by an absence or mutation of the PAH enzyme, which is necessary for the metabolism of the amino acid phenylalanine into tyrosine. Recently, sapropterin dihydrochloride, a synthetic form of tetrahydrobiopterin (BH4), has been introduced as a supplemental treatment to dietary phe control for PKU. Very little is known regarding BH4 treatment and its effect on brain and cognition. The present study represents the first examination of potential changes in neural activation in patients with PKU during BH4 treatment. To this end, we utilized an n-back working memory task in conjunction with functional magnetic resonance imaging (fMRI) to evaluate functional brain integrity in a sample of individuals with PKU at three timepoints: Just prior to BH4 treatment, after 4 weeks of treatment, and after 6 months of treatment. Neural activation patterns observed for the PKU treatment group were compared with those of a demographically-matched sample of healthy non-PKU individuals who were assessed at identical time intervals. Consistent with past research, baseline evaluation revealed impaired working memory and atypical brain activation in the PKU group as compared to the non-PKU group. Most importantly, BH4 treatment was associated with improvements in both working memory and brain activation, with neural changes evident earlier (4-week timepoint) than changes in working memory performance (6-month timepoint)., Highlights • We examine working memory and neural activation in patients with PKU at baseline. • We track behavioral and neural changes related to BH4 treatment in the patients. • BH4 treatment associated with improvement in neural activity at 4-week timepoint. • BH4 treatment associated with improvement in working memory at 6-month timepoint.

The most widely-reported neurologic finding in individuals with early-treated phenylketonuria (PKU) is abnormality in the white matter of the brain. In contrast, much less is known regarding the impact of PKU on cortical gray matter (GM) structures. Presently, we applied advanced morphometric methods to the analysis of high-resolution structural MRI images from a sample of 19 individuals with early-treated PKU and an age- and gender-matched comparison group of 22 healthy individuals without PKU. Data analysis revealed decreased GM volume in parietal cortex for the PKU group compared with the non-PKU group. A similar trend was observed for occipital GM volume. There was no evidence of group-related differences in frontal or temporal GM volume. Within the PKU group, we also found a significant relationship between blood phenylalanine levels and GM volume for select posterior cortical sub-regions. Taken together with previous research on white matter and gray matter abnormalities in PKU, the present findings point to the posterior cortices as the primary site of neurostructural changes related to early-treated PKU.

We appreciate Dr. Finsterer et al. [1] interest in our case report [2]. They express doubts about the diagnosis of Leigh syndrome (LS). Our patient's diagnosis was based on the presence of a known ATPase 6 gene pathogenic mutation (T9176C), previously described in other LS cases [3], [4], [5], [6], [7], [8] , and also in a form of hereditary spastic paraplegia [9] leukodystrophy [10] and bilateral striatal necrosis [11].This mutation has been shown to affect ATP synthesis and the assembly or stability of complex V [9], [12]. There was no consanguinity in her family. The mother and other relatives refused genetic testing for personal (life insurance) and financial reasons. Patient and family also refused to have muscle biopsy done as she clinically improved. Magnetic resonance spectroscopy (MRS) was not performed because genetic testing found a known pathogenic mtDNA mutation. Regarding follow up imaging, brain MRI done 1 year later showed improvement in bilateral basal ganglia and periaqueductal region T2 hyperintensities. Patient did have a staring spell, with decreased oxygen saturation and was started on levetiracetam after her second admission. There was no family history of epilepsy. We agree with Dr. Finsterer et al. comprehensive list of POLG mutation-associated diseases. Regarding treatment effect, we want to reiterate that the exact mechanism by which plasmapheresis or immunoglobulin (IVIG) had beneficial effect in our patient is unknown; however as mentioned in the article, we think that reduced ATP production can increase the mitochondrial transmembrane potential (with resultant hyperpolarization) and increase reactive oxygen species (ROS) production [13], which can in turn activate the necroptosis pathway [14]. Impaired ATP synthesis can also induce necroptosis [15]. Resultant cell necrosis can lead to release of immunogenic material and activate immune and inflammation pathways (inflammasome) [14], [16]. IVIG has been shown to suppress inflammasome-mediated neuronal death in ischemic stroke models [17]. Of note, in mice, mitochondrial complex I mutations have been shown to cause inflammation and retinal ganglion cell death [18], further highlighting the possible relationship between mitochondrial mutations/diseases and inflammation. Additionally, a case of mitochondrial myopathy responsive to intravenous immunoglobulin [19] and patients with acute central nervous system inflammation possibly associated with ND4 and DARS2 mutations and responsive to plasmapheresis, steroids and rituximab have been described in a small report [20]. Further research in the role of autoimmunity and inflammation in mitochondrial disease is needed.

Whereas the impact of early-treated phenylketonuria (ETPKU) on cortical white matter is well documented, relatively little is known regarding the potential impact of this metabolic disorder on deep gray matter structures such as the basal ganglia. The current study used high-resolution (1 mm3) magnetic resonance imaging to investigate bilateral basal ganglia structures (i.e., putamen, caudate nucleus, and nucleus accumbens) in a sample of 13 individuals with ETPKU and a demographically-matched sample of 13 neurologically intact individuals without PKU. Consistent with previous research, we found smaller whole brain volumes in the ETPKU group compared with the non-PKU group. Individuals with ETPKU also had significantly larger putamen volumes than non-PKU individuals. In addition, the degree of putamen enlargement was correlated with blood phenylalanine levels and full scale IQ in the ETPKU group. These findings are consistent with the hypothesis that ETPKU-related increases in phenylalanine lead to decreased central dopamine levels thus impacting dopamine-dependent brain regions such as the putamen that play an important role in cognition.

Phenylketonuria (PKU) is a genetic disorder associated with disruption of prefrontal cortex (PFC) development and executive dysfunction. To date, however, there is little evidence directly linking these two sequelae of PKU. We utilized functional magnetic resonance imaging (fMRI) to evaluate prefrontal functioning in six individuals with early-treated PKU (ETPKU) during performance of an n-back working memory task and compared results with those of six age- and gender-matched neurologically intact individuals. In addition, we evaluated the possible presence of PKU-related disruptions in functional connectivity, as might be hypothesized based on prior reports of white matter injury in individuals with ETPKU. A number of brain regions, nearly half of which were located in the PFC, were found to show atypical neural activity in individuals with ETPKU during working memory performance. We also found decreased connectivity both within the PFC as well as between the PFC and other brain regions in individuals with ETPKU compared with controls. Results from this preliminary study suggest that both prefrontal dysfunction and disruptions in functional connectivity may contribute to PKU-related executive impairment. In addition to advancing our understanding of PKU, the current findings have a broader impact in that PKU is regularly used as a model of early prefrontal dysfunction in the study of other neurodevelopmental disorders (e.g., autism).