# Clinical Profiles, Genetic Variants, and Neurodevelopmental Outcomes Following Liver Transplantation in Maple Syrup Urine Disease: A Study From Palestine

## TL;DR

This study examines how liver transplantation and early diagnosis improve outcomes for Maple Syrup Urine Disease in Palestine, where genetic factors and limited healthcare access are challenges.

## Contribution

The study provides the first comprehensive clinical, biochemical, and genetic characterization of MSUD in the Palestinian population.

## Key findings

- Early liver transplantation is associated with improved neurodevelopmental outcomes and increased leucine tolerance in MSUD patients.
- Founder pathogenic variants in DBT and novel variants in BCKDHA/BCKDHB were identified, highlighting the need for population-specific genetic screening.
- Delayed diagnosis due to lack of newborn screening leads to severe metabolic crises, neurological injury, and higher infant mortality.

## Abstract

Maple syrup urine disease (MSUD) is a rare, autosomal recessive metabolic disorder resulting from a deficiency of the branched‐chain α‐ketoacid dehydrogenase complex. This leads to the accumulation of branched‐chain amino acids and their corresponding ketoacids, causing acute metabolic crises and progressive neurological damage if untreated. The impact of founder variants, high consanguinity, and limited access to metabolic care pose challenges in medically underserved populations, such as in Palestine. We conducted a retrospective analysis of 11 patients from eight Palestinian families referred to the main Metabolic Unit in the West Bank. Clinical data, biochemical profiles, and molecular findings were reviewed to characterize the presentation and outcomes of MSUD. Management strategies, including dietary intervention and liver transplantation, were also evaluated. Acute metabolic crises were the initial presentation in 91% of cases, typically within the first days of life. Diagnostic delay averaged 47 days in families without prior MSUD history, compared to 2.3 days in those with affected siblings. Founder pathogenic variants were identified in multiple unrelated families, reflecting genetic homogeneity due to community structure; novel variants were also detected. Timely diagnosis facilitated early referral and improved outcomes. Patients who underwent liver transplantation, especially when performed early, exhibited favorable developmental trajectories, increased leucine tolerance, and fewer hospitalizations. One participant diagnosed prenatally remained free of metabolic crises until transplantation at age six, with excellent neurocognitive outcomes. This study highlights the importance of integrating prenatal screening and early diagnosis, timely dietary intervention, and liver transplantation to improve MSUD outcomes in resource‐limited settings.

This study provides the first comprehensive clinical, biochemical, and genetic characterization of MSUD in the Palestinian population, revealing a predominance of the classical early‐onset form.Recurrent founder pathogenic variants in DBT, together with novel variants in BCKDHA/BCKDHB, underscore the need for population‐tailored genetic screening in high‐consanguinity settings.Early identification through metabolic screening, founder‐variant mapping, integrated clinical management, and timely liver transplantation was associated with markedly improved outcomes, whereas the absence of newborn screening led to delayed diagnosis, severe metabolic crises, neurological injury, and increased infant mortality.These findings strengthen the evidence that early liver transplantation confers substantial clinical and neurodevelopmental benefits in MSUD, particularly in resource‐limited settings with restricted access to lifelong metabolic care.

This study provides the first comprehensive clinical, biochemical, and genetic characterization of MSUD in the Palestinian population, revealing a predominance of the classical early‐onset form.

Recurrent founder pathogenic variants in DBT, together with novel variants in BCKDHA/BCKDHB, underscore the need for population‐tailored genetic screening in high‐consanguinity settings.

Early identification through metabolic screening, founder‐variant mapping, integrated clinical management, and timely liver transplantation was associated with markedly improved outcomes, whereas the absence of newborn screening led to delayed diagnosis, severe metabolic crises, neurological injury, and increased infant mortality.

These findings strengthen the evidence that early liver transplantation confers substantial clinical and neurodevelopmental benefits in MSUD, particularly in resource‐limited settings with restricted access to lifelong metabolic care.