Novel PGM1 Mutation in Congenital Disorder of Glycosylation Type 1T: A Case Report of Liver Failure and Myopathy

Introduction

Congenital disorders of glycosylation (CDG) are a diverse group of rare inherited metabolic disorders resulting from defects in the enzymatic pathways responsible for glycosylation – an essential process that modulates protein folding, stability, receptor recognition, and intercellular signaling [1]. Given glycosylation’s broad role in cellular and organ system function, CDG can present with a spectrum of clinical manifestations involving hepatic, neurological, muscular, endocrine, hematologic, and gastrointestinal systems [2]. Although the biochemical underpinnings of glycosylation are increasingly understood, many clinicians remain unfamiliar with these disorders due to their rarity and the nonspecific nature of their presentations, often leading to diagnostic delays or misdiagnoses [3].

CDG are broadly classified into 2 types: Type I, which includes defects in the assembly and transfer of glycans onto nascent proteins; and Type II, which encompasses errors in processing attached glycans [4]. Within these categories, over 150 subtypes have been described, each caused by a specific gene mutation and associated with distinct clinical features. CDG Type 1T is a particularly rare and clinically significant subtype caused by biallelic pathogenic variants in the phosphoglucomutase 1 (PGM1) gene [5]. The PGM1 enzyme plays a dual role in energy metabolism and glycoprotein biosynthesis by catalyzing the reversible conversion of glucose-1-phosphate and glucose-6-phosphate [6]. Its deficiency disrupts both glycogen metabolism and glycoprotein synthesis, resulting in multisystemic pathology [7].

The clinical phenotype of CDG Type 1T is highly variable but often includes hepatopathy, coagulopathy, myopathy, endocrine dysfunction, cleft palate, and developmental delay. Hepatic involvement can present with persistent transaminitis, hepatomegaly, coagulopathy, and progressive fibrosis [8]. However, due to overlapping features with more commonly encountered metabolic disorders – such as galactosemia – patients frequently receive a misdiagnosis, particularly in the neonatal and early infantile periods when symptoms first emerge and newborn screening can yield ambiguous results [9].

The motivation for reporting the present case stems from 2 key observations: (1) the child was initially given a misdiagnosis of galactosemia following abnormal newborn screening and was treated with dietary galactose restriction, delaying definitive diagnosis and appropriate management; and (2) once correctly identified as CDG Type 1T, the patient showed marked improvement in hepatic enzymes and coagulation function following initiation of D-galactose therapy. This underscores the diagnostic complexity of CDG Type 1T and the transformative potential of a targeted, evidence-based therapeutic approach.

Despite the emerging literature on PGM1-CDG, few cases have been reported from the Middle East, where high consanguinity rates may increase the prevalence of autosomal recessive conditions [10]. Additionally, limited access to advanced metabolic and genetic testing in resource-constrained settings can impede early diagnosis. Our case highlights the value of combining carbohydrate-deficient transferrin screening with whole exome sequencing to guide accurate diagnosis and personalize treatment [11]. Furthermore, it illustrates the need for early specialist referral and coordinated multidisciplinary management to mitigate irreversible organ damage, such as liver fibrosis.

Case Report

PATIENT BACKGROUND AND EARLY EVALUATION:

A 20-month-old boy of Middle Eastern descent was born at term to healthy, consanguineous first-degree relatives. Birth weight was 3 kg. At delivery, the neonate exhibited multiple dysmorphic features, including a brachycephalic skull, symmetrically up-slanting palpebral fissures, bilaterally low-set ears, a broad and flattened nasal bridge, an elongated philtrum, and a midline cleft palate. Facial asymmetry was not observed, and features were judged to be moderate in severity. He developed respiratory distress shortly after birth, requiring a 10-day NICU admission.

Newborn screening showed reduced galactose-1-phosphate uridyltransferase (GALT) activity, leading to a presumptive diagnosis of classic galactosemia. The patient was immediately placed on a lactose-free formula and discharged in stable condition.

During subsequent months, he exhibited global developmental delay, particularly in gross motor skills, and persistent elevation of liver enzymes. Despite lactose restriction, hepatic transaminases remained markedly elevated, and coagulation profiles were abnormal.

FAMILY HISTORY:

Notably, a paternal cousin experienced similar hepatopathy and was previously labeled as having “autoimmune hepatitis.” Genetic testing was not performed for that relative, and thus CDG or related metabolic disorders could not be confirmed or excluded.

CLINICAL COURSE AND REFERRAL:

When the patient was 20 months of age, referral to a tertiary care center was made for unresolved hepatopathy, developmental delay, and abnormal laboratory findings. Physical examination confirmed the dysmorphic features, palpable hepatomegaly (2 cm below the costal margin), and delayed ambulation. No splenomegaly, ascites, or jaundice were detected. Growth parameters were normal.

DIAGNOSTIC EVALUATION:

Carbohydrate-deficient transferrin testing demonstrated an abnormal glycoform distribution, consistent with Type I CDG. Whole exome sequencing subsequently identified a homozygous missense variant in PGM1: c.[XXXXA>G]; p.[ArgXXXGln], classified as a variant of uncertain significance. When integrated with the clinical phenotype and biochemical findings, the variant supported a diagnosis of CDG Type 1T.

Laboratory test results at admission revealed aspartate aminotransferase was 1980 U/L, alanine aminotransferase was 695 U/L, and prothrombin time was partially prolonged, corrected by vitamin K. Creatine kinase was mildly elevated. Ultrasound showed increased hepatic echogenicity, and biopsy demonstrated 60% macrovesicular steatosis, ballooning degeneration, mild lobular inflammation, and bridging portal fibrosis. Autoimmune markers were negative.

TREATMENT AND OUTCOME:

After multidisciplinary review, oral D-galactose was initiated at 0.5 g/kg/day and titrated to 1.5 g/kg/day over 6 weeks. Vitamin K and supportive care were provided. No adverse events were noted. By discharge at 51 days, aspartate aminotransferase had fallen to 385 U/L and alanine aminotransferase to 210 U/L, with normalization of prothrombin time. Creatine kinase remained mildly elevated, indicating incomplete muscle response. Plans for cleft palate repair were deferred until stabilization.

Genetic counseling was offered, highlighting the autosomal recessive inheritance and 25% recurrence risk. Long-term follow-up was arranged, including neurological, endocrine, and developmental surveillance.

Discussion

This case illustrates the diagnostic complexity and therapeutic potential associated with CDG Type 1T, caused by PGM1 deficiency. CDG Type 1T poses a clinical challenge due to its multisystemic manifestations and phenotypic overlap with more common metabolic disorders, such as galactosemia and glycogen storage diseases [12,13]. In this patient, the initial diagnosis of galactosemia based on reduced GALT activity delayed recognition of the underlying glycosylation disorder. The abnormal carbohydrate-deficient transferrin profile, combined with whole exome sequencing, enabled diagnostic clarification. Importantly, whole exome sequencing identified a homozygous PGM1 missense variant, (c.[XXXXA>G], p.[ArgXXXGln]), which has not been previously reported and is currently classified as a variant of uncertain significance. Although this limits absolute diagnostic certainty, the congruence between clinical phenotype, biochemical abnormalities, and molecular findings strongly supports pathogenicity [14].

The hallmark of CDG Type 1T in this case was severe hepatic dysfunction, with transaminase levels exceeding 1900 U/L and evidence of portal fibrosis. The therapeutic use of oral D-galactose – aimed at bypassing the glycosylation defect – resulted in marked improvement in liver function and coagulation profiles [15]. This supports the existing literature suggesting that galactose supplementation has hepatic benefits in select CDG subtypes. The normalization of prothrombin time and substantial decline in transaminase levels within weeks of therapy suggest enhanced glycoprotein biosynthesis in hepatic tissue, facilitated by exogenous galactose [16].

Beyond the immediate hepatic and muscular outcomes, this case emphasizes the importance of long-term multidisciplinary follow-up. Children with CDG Type 1T are at risk for progressive neurological, endocrine, and developmental complications, including hypogonadism, growth delay, intellectual disability, and motor impairment [12]. Regular monitoring of neurodevelopmental milestones, hormonal status, and cognitive function is therefore essential to optimize long-term outcomes.

However, the response of muscle enzymes, particularly creatine kinase, was only partial. Several mechanisms may explain this observation. Muscle tissues may have lower uptake efficiency for supplemental galactose, or they may express tissue-specific isoforms of glycosylation enzymes not fully responsive to therapy [17,18]. Additionally, longstanding structural muscle damage may not be reversible with metabolic correction alone. This disparity in treatment response underscores the need for future research into adjunctive therapies for extrahepatic manifestations of CDG [19].

This case contributes to the literature by documenting a rare presentation of CDG Type 1T from the Middle East, where data remain limited despite a high prevalence of consanguinity. The identification of a homozygous PGM1 variant in a clinically complex child highlights the importance of early genetic evaluation when initial diagnoses do not account for the full clinical spectrum. Furthermore, it demonstrates the potential reversibility of liver pathology with prompt metabolic intervention, highlighting the importance of clinician awareness and access to specialized diagnostics in resource-constrained environments.

Conclusions

This case underscores the diagnostic complexity of CDG Type 1T, particularly when initial findings mimic more common metabolic disorders, such as galactosemia. Whole exome sequencing identified a homozygous PGM1 variant, (c.[XXXXA>G], p.[ArgXXXGln]), currently classified as a variant of uncertain significance, yet supported by the patient’s clinical and biochemical features. Initiation of D-galactose therapy resulted in marked hepatic improvement, including normalization of coagulation parameters and substantial reduction of transaminase levels. However, the muscular response was incomplete, with persistently elevated creatine kinase levels, highlighting the limitations of current treatment.

This case emphasizes the importance of early recognition, genetic confirmation, and multidisciplinary management in children with unexplained liver dysfunction, especially in regions with high consanguinity and limited diagnostic resources. Future research is needed to validate the pathogenicity of novel variants, explore therapeutic options for extrahepatic manifestations, such as myopathy and endocrine dysfunction, and evaluate long-term outcomes to better inform prognosis and patient care.