TANGO2 deficiency disease (TDD) is a rare genetic disorder estimated to affect ∼8000 individuals worldwide. It causes neurodegeneration often accompanied by potentially lethal metabolic crises that are triggered by diet or illness. Recent work has demonstrated distinct lipid imbalances in multiple model systems either depleted for or devoid of the TANGO2 protein, including human cells, fruit flies and zebrafish. Importantly, vitamin B5 supplementation has been shown to rescue TANGO2 deficiency-associated defects in flies and human cells. The notion that vitamin B5 is needed for synthesis of the lipid precursor coenzyme A (CoA) corroborates the hypothesis that key aspects of TDD pathology may be caused by lipid imbalance. A natural history study of 73 individuals with TDD reported that either multivitamin or vitamin B complex supplementation prevented the metabolic crises, suggesting this as a potentially life-saving treatment. Although recently published work supports this notion, much remains unknown about TANGO2 function, the pathological mechanism of TDD and the possible downsides of sustained vitamin supplementation in children and young adults. In this Perspective, we discuss these recent findings and highlight areas for immediate scientific attention.

TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD.
Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review.
Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation.
We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.

OBJECTIVE: This study aimed to investigate the frequency and status of depression and anxiety among mothers of children with inborn errors of metabolism (IEM) who were on a restricted diet and previously experienced metabolic crises.
METHODS: This cross-sectional multicenter descriptive study included 93 children with IEM who were on restricted diet. The patients were divided into two groups: those who had experienced metabolic crises (n=44, urea cycle defect, organic acidemia, maple syrup urine disease, hereditary fructose intolerance) and those who had not experienced previous metabolic crises (n=49; phenylketonuria, galactosemia, and non-ketotic hyperglycinemia). The control group comprised 37 healthy children. The mothers of the patients and control participants answered a questionnaire about their and their children\'s demographic and clinical characteristics and completed the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI-S and STAI-T).
RESULTS: The maternal BDI, STAI-S, and STAI-T scores were 6.3±5.2, 36.1±11.2, and 39.9±8.8, respectively, in the control group. The maternal BDI, STAI-S, and STAI-T scores of the children who had experienced (19.2±9.7; 44.0±12.4; 47.9±10.6) and those who had not experienced (13.9±9.1; 40.7 ±8.6; 45.3±8.3) a crisis were significantly higher than for the controls. The BDI score was significantly higher for the mothers of children who had experienced a crisis (p=0.011), whereas no significant difference was determined between the two patient groups regarding STAI-S and STAI-T scores. The mothers of four children who had experienced metabolic crises were on antidepressant therapy.
CONCLUSIONS: Although their children were on a similar restricted diet, the mothers of children who previously experienced or who had the risk of experiencing metabolic crises had higher depression scores as compared with the mothers of children who did not experience a previous crisis. Early supportive therapy may be required for the families of these patients to lower the burden of stress.

Subarachnoid hemorrhage is frequently associated with poor prognoses. Three different hemodynamic phases were identified during subarachnoid hemorrhage: oligemia, hyperemia, and vasospasm. Each phase is associated with brain metabolic changes. In this review, we correlated the hemodynamic phases with brain metabolism and potential treatment options in the hopes of improving patient prognoses.