Also known as carbohydrate deficient glycoprotein syndrome type 1j
A rare, inherited condition primarily affecting the nervous system caused by N-linked glycosylation disruption. Symptoms typically manifest in infancy with two phenotypes: congenital myasthenia syndrome (CMS) and encephalopathy. Characteristics are muscle weakness, hypotonia (low muscle tone), developmental delay, cognitive and speech impairments, and seizures.
Symptoms
DPAGT1-CDG is a rare, potentially severe inherited condition that is caused by genetic mutations in the DPAGT1 gene and primarily affects the nervous system. Most patients develop symptoms of the disorder during infancy and some already show reduced fetal movement activity during pregnancy (fetal hypokinesia). However, there are also reports of patients who did not develop symptoms until childhood.
Patients with DPAGT1-CDG may present with one of two phenotypes: one that mainly affects the communication between nerve and muscle cells, characterized by muscle weakness and fatigue (congenital myasthenic syndrome, CMS), or a severe brain disease (encephalopathy) with early death in the context of a multi-system disorder. Overall, patients with DPAGT1-CDG can show a wide spectrum of very different physical and psychiatric/psychological symptoms.
The most common symptoms of patients with DPAGT1-CDG are weakness of the muscles and decreased muscle tone (hypotonia), developmental delay, cognitive impairment (ranging from mild to severe) and seizures. Other features that are present in some, but not all, patients with DPAGT1-CDG include speech problems, feeding difficulties and behavioral problems (for example aggressive behavior). Many show distinct facial features (facial dysmorphism), misaligned eyes with an inward turning of one or both eyes (esotropia), cataracts, an abnormally small head (microcephaly), a small lower jaw (micrognathia), a tall and narrow roof of the mouth (arched palate), a single line that runs across the palm of the hand (flexion crease), stiffening of the joints (joint contractures), and a permanent curving of the pinkie finger (clinodactyly of the 5th digit). A few patients also show respiratory problems (apnea and respiratory deficiency), kidney abnormalities and liver symptoms.
Brain imaging shows structural abnormalities of the brain, including an often small, underdeveloped cerebellum (cerebellar hypoplasia). Laboratory investigations may occasionally reveal elevated levels of a muscle enzyme called creatine kinase (CK).
Adults with DPAGT1-CDG have a significantly different presentation of the disease in comparison to children with the disorder. They are often normal at birth and may begin to exhibit seizures and aggressive behavior in early childhood (between 2-5 years of age). They also often have a symmetrical weakness of the upper and/or lower limbs (proximal weakness) and cloudiness of the lens of the eye, which causes impaired vision (cataract). Behavioral and/or psychiatric problems are present in some, but not all, adult DPAGT1-CDG patients (a diagnosis of mental illness has been reported in two adults with DPAGT1-CDG).
In contrast to adult patients, the infantile type of DPAGT1-CDG presents predominantly with a neuromuscular disorder that causes weakness in the skeletal muscles (myasthenia gravis). There are currently no reports regarding behavioral problems in the early onset form of DPAGT1-CDG.
As of 2021, there are 40 cases with DPAGT1-CDG that have been reported in medical literature.
Diagnosis
DPAGT1-CDG can be diagnosed using a screening test for CDG called “transferrin isoelectric focusing”, which detects abnormal levels of a glycoprotein called transferrin in the blood. All patients with the multi-system presentation show abnormalities in this test (a specific “type 1” pattern). However, in half of the patients with congenital myasthenic syndrome, serum transferrin pattern is normal.
An additional diagnostic tool for DPAGT1-CDG is the analysis of sugar chains attached to proteins in the blood (serum N-glycans), which can be tested by different methods in blood and fibroblasts.
For congenital myasthenic syndromes (CMS), the disturbed transmission of signals between nerves and muscles is investigated by the analysis of the activity of individual muscle fibers (single fiber EMG) or nerve stimulation tests. For DPAGT1-associated CMS, it is also important to verify the absence of auto-antibodies, which can be present in other myasthenic syndromes. The presence of certain abnormalities in the muscle biopsy (tubular aggregates) can help to distinguish between congenital myasthenic syndromes that respond to certain treatments (acetylcholinesterase inhibitors) and the ones that do not.
Genetic testing is needed to confirm the diagnosis. Individuals with DPAGT1-CDG have two faulty copies of the DPAGT1 gene.
Treatment and Prognosis
Currently, there are no FDA-approved curative treatments available for DPAGT1-CDG. However, there are many studies that are investigating effective therapeutic targets for treating DPAGT1-CDG. Research studies have also reported that DPAGT1-CDG patients with the congenital myasthenic presentation respond favorably to acetylcholinesterase inhibitor drugs such as pyridostigmine.
Besides these treatment options, most treatment of DPAGT1-CDG is aimed at easing and alleviating the symptoms experienced by the patient (“symptomatic” treatment) and at the prevention of complications.
The oldest individual with DPAGT1-CDG that has been described in medical literature was 34 years old when his case was reported in 2019.