A Case of HNRNPU‐Related Neurodevelopmental Disorder Presenting With Acute Encephalopathy and Basal Ganglia Lesions

ABSTRACT

We report a case in which a girl diagnosed with HNRNPU‐associated neurodevelopmental disorder presented with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and generalized hypotonia accompanied by chorea‐like involuntary movements. On the first day of hospitalization, she presented with fever and generalized clonic seizures. Twenty four hours later, she continued to experience impaired consciousness and generalized hypotonia. Her consciousness improved gradually, but chorea‐like involuntary movements of the limbs were observed. From the seventh day of hospitalization, the patient repeatedly experienced difficulty in making eye contact for 20–30 s for 2–3 days. Brain MRI with diffusion‐weighted imaging revealed hyperintensity from the bilateral frontal cortex to subcortical white matter and the bilateral caudate nuclei. This patient presented with chorea‐like involuntary movements and generalized hypotonia, and was unable to perform antigravity movements. HNRNPU‐related neurodevelopmental disorders often present with congenital hypotonia. When affected children develop acute encephalopathy associated with basal ganglia lesions, the synergistic effect of these conditions may exacerbate the hypotonia.

1. Introduction

Heterozygous loss‐of‐function variants in heterogeneous nuclear ribonucleoprotein U (HNRNPU) cause early‐onset developmental and epileptic encephalopathy accompanied by multiple congenital anomalies.

We report a girl with HNRNPU‐related neurodevelopmental disorder who also exhibited pharyngeal stenosis and laryngomalacia [1]. At 3 years of age, she developed clinical features suggestive of acute biphasic encephalopathy with biphasic seizures and late reduced diffusion (AESD), associated with basal ganglia lesions and generalized hypotonia with chorea‐like movements.

Although AESD has been reported in individuals with HNRNPU‐related disorders [2], to our knowledge, generalized hypotonia has not been previously reported in patients with HNRNPU‐related disorders who developed AESD associated with basal ganglia lesions.

2. Case Report

A 3‐year‐old girl with HNRNPU‐related neurodevelopmental disorder (NM_031844.3:c.797T>A) presented with congenital hypotonia, epilepsy, oropharyngeal stenosis, tracheomalacia, cleft soft palate, and otitis media with effusion. From 1 year of age, she experienced 2–3 min epileptic seizures every 2 months, characterized by staring, generalized weakness, and cyanosis of the lips. She was regularly treated with sodium valproate and nitrazepam. She underwent tracheostomy at 2 years of age and gastrostomy at 3 years of age. There was no history of severe bacterial infection, and she had received four doses of the Haemophilus influenzae type b (Hib) vaccine.

Her daily care included respiratory management using a heat and moisture exchanger during the day and continuous positive airway pressure during sleep. Due to severe oral hypersensitivity, oral intake was not possible, and enteral nutrition was provided via gastrostomy. Regarding her developmental milestones, she gained head control at 6 months, sat without support at 8 months, and walked independently at 2 years 7 months. The family history was unremarkable; she was the third daughter.

At the onset of the febrile episode, she developed a fever of 39°C and experienced two seizures 6 h apart. One hour after the second seizure, she developed generalized clonic convulsions with persistent conjugate deviation of the eyes to the right upper quadrant and was transported emergently to our hospital. On arrival, midazolam (5 mg, twice) was administered oromucosally, followed by intravenous midazolam (0.2 mg/kg) and phenobarbital (20 mg/kg), which terminated the convulsions, although ocular deviation persisted. A further intravenous dose of midazolam (0.2 mg/kg) resolved the deviation. The total duration of convulsions was approximately 66 min. Laboratory findings at admission revealed: WBC 21 520/μL (neutrophils 48.6%) and CRP 1.35 mg/dL. Cerebrospinal fluid examination showed 0 cells/μL.

After admission (Table 1), tracheal secretions gradually increased. She was diagnosed with complex febrile seizures secondary to acute upper respiratory tract inflammation, and no antibiotics were initially administered. Brain MRI performed 24 h after admission revealed no abnormalities (Figure 1a). However, her consciousness fluctuated markedly (Glasgow Coma Scale 3–13), with persistent generalized hypotonia unable to perform antigravity movements, leading to a diagnosis of acute encephalopathy. Steroid pulse therapy with methylprednisolone (30 mg/kg/day for 3 days) was initiated. By day three, her fever subsided and consciousness improved (Glasgow Coma Scale 13–15), although hypotonia persisted and intermittent chorea‐like movements of the limbs were observed. Hypotonia was predominantly axial; in the supine position, she was in a frog position, and head lag was observed on the pull‐to‐sit maneuver. The patellar tendon reflexes were slightly hyperactive. The involuntary movements were characterized by sudden, rapid elevation of both upper limbs or brisk snapping movements from the elbow to the upper arm, followed by a slow return to the resting position, repeatedly recurring. During these episodes, the lower extremities were intermittently extended or moved in a flapping manner, with each episode lasting approximately 30–60 s. In addition, sudden elevation of the right upper limb was frequently observed. The movements were not suppressible, and the patient repeatedly struck the bed rails with the affected arm; therefore, protective padding was applied to the bed rails to prevent injury. By day four, her cough and tracheal secretions decreased. On day five, a diffusion‐weighted MRI (Figure 1b) revealed hyperintense signals from the bilateral frontal cortices to subcortical white matter, more prominent on the right. No abnormalities of the cerebellum or brainstem were observed on MRI, and the spinal cord was not assessed. On the same day, the blood cultures were positive for H. influenzae , and intravenous ampicillin was started. On day seven, she exhibited brief episodes (20–30 s) of loss of eye contact and finger rigidity over 2–3 days. Although electroencephalography (EEG) was not performed at that time, the clinical features, together with the brain MRI findings, were considered consistent with late seizures of AESD, and the patient was diagnosed with suspected AESD. On day 8, chorea‐like involuntary movements increased during nocturnal rest, persisted for approximately 10 min, and repeatedly recurred after intervening quiescent periods, ultimately disappearing with the onset of sleep. By day 10, the involuntary movements had improved. On day 11, a diffusion‐weighted MRI (Figure 1c) demonstrated new hyperintense lesions in the bilateral caudate nuclei. A full‐day EEG showed paroxysmal sharp waves intermittently in the F7 and F8 regions during light sleep, considered pre‐existing, with no new ictal activity. Notably, EEG was not performed during the acute phase. Rehabilitation was initiated, and she was discharged on hospital day 24. One month later, involuntary movements had resolved, and she was able to suck her thumb; however, generalized hypotonia persisted. Of note, serotyping of H. influenzae was not performed.

TABLE 1.

Timeline of neurological findings.

Abbreviations: MDZ, midazolam; PB, phenobarbital.

FIGURE 1.

Diffusion‐weighted MRI findings. (a) Day 2: No abnormalities observed. (b) Day 5: Hyperintense lesions from the bilateral frontal cortex to subcortical white matter, more prominent on the right. (c) Day 11: Newly developed hyperintense signals in the bilateral caudate nuclei. No abnormalities of the putamen, globus pallidus, thalamus were observed on MRI.

3. Discussion

The notable feature of this case is the presence of basal ganglia lesions in a child with HNRNPU‐related neurodevelopmental disorder who presented with symptoms suggestive of AESD. However, in this case, restricted diffusion mainly in subcortical white matter (“bright tree appearance”) was not observed on MRI, and although a decreased level of consciousness was noted during the subacute phase, EEG was not performed. Therefore, there is no definitive evidence of late seizures, and a confirmed diagnosis of AESD cannot be established. Accordingly, this case is considered to be suspected AESD or an unclassifiable type of encephalopathy.

AESD is usually defined by prolonged febrile seizures followed by late seizures and restricted diffusion mainly in subcortical white matter (“bright tree appearance”) on MRI days 3–14. When the bright tree appearance is not observed in the acute phase, as in the present case, the following convalescent findings are supportive of possible AESD: subcortical hyperintensity on T2/FLAIR within the distribution typically observed in bright tree appearance [3]. In this case, hyperintense lesions extending from the cortex to the subcortical white matter on MRI were observed between days 7 and 11 of hospitalization, supporting the likelihood of AESD. However, basal ganglia involvement is rare in AESD, and therefore this case was considered atypical for AESD.

Although the patient did not exhibit the typical late seizures characteristic of AESD, the loss of eye contact on day 7 was interpreted as either recurrent seizures or worsening impaired consciousness, which is compatible with AESD. Nevertheless, to establish a definitive diagnosis of AESD, continuous electroencephalographic monitoring should have been performed at that time. A limitation of this case is the lack of electroencephalographic data during the peak of symptoms.

Because this case lacked the typical MRI finding (i.e., bright tree appearance) and late seizure of AESD, differential diagnoses other than acute encephalopathy needed to be considered. Based on the differences from other acute encephalopathies shown in Table 2, this case was classified as acute encephalopathy. Within the classification of acute encephalopathy, this case was considered most consistent with AESD or unclassified acute encephalopathy.

TABLE 2.

Differential diagnosis of encephalitis.

Category	Disease	Difference of encephalopathy
Infection	Encephalopathy/meningitis	Elevated cerebrospinal fluid cell count
	Brain abscess	Detected by imaging test
Inflammatory disease	Demyelinating diseases	Detected by imaging test
	Autoimmune diseases	Elevated cerebrospinal fluid cell count
Intracranial disease	Intracranial hemorrhage/vascular disease	Detected by imaging test
Metabolic disease		Elevated serum ammonium level
Addiction		History of excessive medication
Organ failure		Detected by blood test
Others	Febrile convulsion, heat stroke	Determined from medical history

The differential diagnoses for hypotonia in this case include eight possibilities; however, the first three are likely interrelated. First, central hypotonia associated with encephalopathy may result from widespread dysfunction of the supplementary motor area and prefrontal cortex [4]. Second, caudate nucleus involvement may cause disinhibition of the brainstem, leading to activation of the reticulospinal tract, which suppresses muscle tone via inhibitory spinal interneurons [5, 6], resulting in central hypotonia associated with encephalopathy. Third, pre‐existing congenital hypotonia related to HNRNPU‐related neurodevelopmental disorder may have contributed to the severity and prolonged course of central hypotonia associated with encephalopathy. Fourth, acute cerebellar ataxia was considered unlikely. Although acute cerebellar ataxia typically occurs several days after viral infection, reports following bacterial infection, as in the present patient, are rare, and symptoms usually do not persist for several months. Fifth, postictal seizure state was considered unlikely. Postictal hypotonia is caused by neuronal fatigue and excessive inhibition, and patients usually recover within 5–30 min, although symptoms may persist for 1–2 days [7]. In this case, hypotonia persisted for several months, making this diagnosis unlikely. Sixth, critical illness polyneuropathy/myopathy; seventh, spinal shock were considered unlikely. Although severe systemic illness can cause hypotonia due to peripheral nerve or spinal cord dysfunction, the presence of chorea‐like involuntary movements during the hypotonic phase made spinal cord pathology unlikely. Eighth, hypoxic–ischemic encephalopathy was considered unlikely. In hypoxic–ischemic encephalopathy, diffusion‐weighted imaging typically shows hyperintensity in the acute phase that diminishes in the chronic phase. In this case, no significant abnormalities were observed on acute‐phase MRI, whereas hyperintensity appeared in the subacute to recovery phase.

Matsubara et al. [4] reviewed and compared 10 reported cases of AESD with basal ganglia lesions accompanied by involuntary movements. The involuntary movements included dystonia (6 cases), chorea (2 cases), choreoathetosis (1 case), athetosis (2 cases), and ataxia (1 case). In seven cases with onset during the acute phase, symptoms improved within 2–8 weeks, whereas in three cases with chronic‐phase onset, involuntary movements were observed 3–9 years after disease onset. Basal ganglia lesions were identified on MRI or SPECT in eight cases, and the presence of basal ganglia involvement was associated with a high incidence of involuntary movements. One of the 10 reported cases with thalamic and basal ganglia lesions presenting with choreoathetosis showed hypotonia from days 6 to 15 after onset, resembling the clinical course of the present case. Although the reason for the bimodal timing of involuntary movement onset (acute vs. chronic phase) remains unclear, the present case similarly exhibited chorea‐like movements during the acute phase.

Differential diagnoses for involuntary movements include postictal seizure state, Sydenham chorea following streptococcal infection, and autoimmune encephalitis (e.g., anti‐NMDA receptor encephalitis). Because this patient developed symptoms after pneumococcal infection, Sydenham chorea was considered unlikely. Consistent with the findings reported by Matsubara et al. [4], we concluded that the movement disorder in this case was most likely attributable to AESD with caudate involvement.

AESD may be more prone to develop in patients with underlying developmental and epileptic encephalopathy [7]. More cases are needed to elucidate the pathogenesis of AESD in HNRNPU‐related neurodevelopmental disorders.

In retrospect, antibiotic therapy should have been initiated at an earlier stage. Although acute encephalopathy is most commonly associated with viral infections, it is important to keep in mind that it can also occur secondary to bacterial infections. In addition, because this patient developed invasive H. influenzae infection despite prior Hib vaccination, serotyping of H. influenzae should have been performed to determine the specific cause.

Ethics Statement

All procedures performed in this paper are in accordance with the ethical standards of the institutional committee on human research.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Research data are not shared.