DYSMORPHIC FEATURES IN A PATIENT WITH GLYCOGEN STORAGE DISEASE TYPE 4: A RARE PHENOTYPIC VARIATION

Glycogen storage disease type 4 (GSD4) is a rare autosomal recessive disorder caused by a deficiency
of glycogen branching enzyme (GBE). The GBE1 gene provides instructions for making glycogen branching
enzyme, which is involved in the final step of glycogen production. Glycogen is the main source of stored
energy in the body.
Pathogenic variants of GBE1 causes accumulation of abnormal glycogen in various tissues, especially the
liver, skeletal muscle, heart, skin, and central nervous system.
The neuromuscular subtype of GSD4 is characterized by early onset muscle weakness and wasting. While
dermatologic manifestations have been previously reported in GSD4, dysmorphic features are not typically
associated with this condition.
We report a case of a patient with GSD4 neuromuscular subtype who exhibits dysmorphic features,
including a webbed neck, low set ears, and increased hair growth on the back of the neck. The patient was
examined at the Medical Genetics and Prenatal Diagnostics Department of Latvian Children's Clinical
University Hospital, where genetic testing was performed using new generation sequencing.
29-year-old patient came to the Genetic consultation with complaints about gait and coordination
problems. The patient experiences symptoms since the early childhood – her childhood diagnosis –
arthrogryposis. Patient started walking at the age of 5. Intelligence is normal. From the age of 22 patient
started to notice a decrease in muscle strength, followed by depression, which further aggravated the
symptoms. Now, the patient walks about 400m a day, then experiences joint pain and muscle stiffness.
During the last year, the progression of the disease has been more pronounced. Additionally, memory
disturbances have appeared. Similar symptoms had not been observed in the family history.
Genetic testing revealed two likely pathogenic variants in the GBE1 gene, confirming the diagnosis of
GSD4: GBE1 c.1259del, p.(Cys421AlafsTer15) and GBE1 c.784G>A, p.(Arg262His). In gnomAD both of the
variants are located on different haplotypes, these two variants are likely compound heterozygous (in trans).
While patient’s neurological symptoms are strongly correlated with the known phenotype of the disease,
dysmorphic features are not typically associated with GSD4 and it is unclear whether they are directly related
to the genetic variants or represent an unrelated condition.
This is the second case that describes a patient with GSD4 neuromuscular subtype who also has
dysmorphic features – webbed neck and increased hair growth on the back of the neck. While the association
between GSD4 and dysmorphic features is unclear, this case highlights the importance of considering this
possibility in patients with GSD4. The identification of two likely pathogenic variants in the GBE1 gene
through new generation sequencing confirms the diagnosis of GSD4 in this patient. Further monitoring and
management of the patient's symptoms are warranted