Clinical Reasoning: A 14-year-old girl with headache, seizures, and confusion

Section 1

A 14-year-old girl without any relevant medical history was transferred to our institution due to worsening headache along with nausea, vomiting, and generalized tonic-clonic (GTC) seizures for 7 days. She was also noted to have multiple psychological and behavioral abnormalities for 1 day. Her headache was described as severe holocephalic pain aggravated when lying down and alleviated after vomiting. No throbbing or phonophobia/photophobia was observed. Her seizures occurred once or twice a day, lasting about 1 minute each and resolving spontaneously. Symptoms were refractory to rotundine (dopamine D1 receptor antagonist), azasetron (antiemetic), mannitol, oxcarbazepine, and phenobarbital.

Psychological and behavioral abnormalities were noted including singing, raving, crying, and laughing intermittently. On physical examination, exotropia, hyperpigmentation of the skin, and long fingers were observed. On neurologic examination, the patient was unable to follow commands but responded to noxious stimuli. Funduscopic examination revealed papilledema. Plantar responses were extensor bilaterally.

D-dimer was high (2.72 mg/L, normal <0.5 mg/L), which suggested hypercoagulation and thrombogenesis. CT of head and intracranial arteries showed cerebral infarction and subarachnoid hemorrhage (figure 1, A) without arterial aneurysm or vascular malformation. Lumbar puncture revealed an opening pressure that was elevated at 300 mm of water, elevated red blood cells (>1,000 cells/mm³), and elevated white blood cells (about 20 cells/mm³). CSF glucose, chloride, and protein were normal.

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Figure 1 Images of the reported case

(A) Brain CT shows cerebral infarction (triangle), subarachnoid hemorrhage (bold arrow), and thrombus of superior sagittal sinus (thin arrow). (B) CT venography (CTV) reveals cerebral venous sinus thrombosis (CVST) with filling defect of the right sigmoid sinus and right lateral sinuses (white arrow). (C) CTV after a month of treatment; the right sigmoid sinus and right lateral sinuses unobstructed but narrowed (white arrow). (D) X-ray suggests that joint space of bilateral wrist was narrowed. (E) The patient's long fingers. The circles show hyperpigmentation of skin, especially in the interphalangeal joints. (F) Histopathologic study of the patient's slightly darker skin reveals hyperkeratosis (yellow arrowhead) and verrucous hyperplasia in the basal layer of the epidermis (white arrowhead) (magnified 10 × 10 times under the microscope). (G) Pedigree of the family with homocystinuria. (H) Gene direct sequencing identified 2 novel compound heterozygous mutations: c.551T>C (p.L184P) and c.949A>G (p.R317G) (indicated by the red arrow). Ⅰ-1: Heterozygous mutations of c.949A>G, the c.551 TT is normal; Ⅰ-2: heterozygous mutations of c.551T>C, the c.949AA is normal; Ⅱ-1, Ⅱ-2: compound heterozygous mutations of c.551T>C and c.949A>G. (I) Orthologous protein sequence alignment of cystathionine β-synthase from different species. The mutated residue showing conservation is shaded in red. Red shaded amino acids proteins show that the 2 novel missense mutations occurred at highly conserved positions in these species. DD = Dictyostelium discodeum; HS = Homo sapiens; MM = Mus musculus; OC = Oryctolagus cuniculus; RN = Rattus norvegicus, splice isoform Ⅲ; SC = Saccharomyces cerevisiae; TC = Trypanosoma cruzi.

A continuous EEG showed diffuse background slowing with epileptiform discharges including frequent spikes and sharp waves present over the bilateral frontal and temporal regions. CT venography (CTV) revealed cerebral venous sinus thrombosis (CVST) with filling defects of the sigmoid and right lateral sinuses (figure 1, B). There was no family history of headache, epilepsy, or CVST.

Section 2

The primary cause for CVST is usually hypercoagulability due to acquired and genetic risks (table 1).¹ The patient had no evidence of common risks in table 1 such as infection, vitamin deficiency, abnormal protein C or protein S, estrogen-related factors, or others. However, she did have high level of plasma total homocysteine (Hcy) (149.40 µmol/L, normal <15 µmol/L).

Hcy causes approximately 4.5% of cases of CVST.² It is a nonessential but indispensable sulfur-containing amino acid in humans. Hcy levels in the bloodstream can rise in 3 different ways³: (1) protein structure modifications; (2) oxidative stress induction; and (3) excitotoxicity. Hyperhomocysteinemia (HHcy) can lead to CVST and thromboembolism⁴ by causing prothrombotic conditions, endothelial dysfunction, and impaired thrombolysis. HHcy can also result in multisystem damage⁵ (table 2) by the 3 main pathways mentioned above.³

In this case, the patient had CVST and multisystem dysfunction due to HHcy (table 2), including ocular anomalies, skeletal system deformities (figure 1, D), skin diseases (figure 1, E and F), and CNS abnormalities.

Section 3

The common causes for HHcy can be divided into exogenous factors such as overintake of cysteine (Cys) or methionine (Met) or dietary deficiencies of vitamins B₆, B₁₂, or folate⁶ (figure 2). Exogenous factors of HHcy were considered unlikely—there was no history of dietary restrictions or overuse of vitamins. However, the patient's older sister (Ⅱ-1 in the pedigree of figure 1G) also had multiple medical problems (table 2). Thus, the patient's HHcy may have been due to inherited factors, which tend to be a considerable cause of HHcy.

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Figure 2 The biochemical metabolism of homocysteine (Hcy)

(A) Hcy and serine can transfer to cystathionine, and the reactions are catalyzed by vitamin B₆ and cystathionine β-synthase (CBS) resynthesis. (B) Remethylation to methionine of Hcy pathways. Vitamin B₁₂, betaine, and betaine homocysteine methyltransferase (BHMT) are independent. (C) In the cycle of methylenetetrahydrofolate (THF), vitamin B₂ and methylenetetrahydrofolate reductase (MTHFR) are indispensable. Cys = cysteine; Met = methionine; MS = methionine synthase; MSR = methionine synthase reductase; SAM = S-adenosyl methionine; SAH = S-adenosyl homocysteine.

For our patient, we first screened for common genetic defects and biochemical abnormalities. Investigations revealed elevated plasma Met (437.77 µmol/L) without a normal level of methylmalonic acid on plasma aminoacid chromatomatography. These results were consistent with cystathionine β-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) deficiency⁶ (table 3).

To confirm the diagnosis,⁷ an experimental study was conducted using all exons of CBS and MTHFR genes in the pedigree (figure 1, G). We found novel compound heterozygous mutations of the CBS gene, c.551T>C (p.leucine 184 proline) and c.949A>G (p.arginine 317 glycine) (figure 1, H), which were coseparated and predicted as damaged and possibly damaged according to SIFT (sift.jcvi.org/) and PolyPhen (genetics.bwh.harvard.edu/pph2/). Interestingly, the 2 novel mutations occurred at highly conserved positions across different species (figure 1, I). To our knowledge, this is the first time this has been reported in the literature, including from the National Heart Blood and Lung Institute Exome Sequencing Project, 1000 Genomes Project, or the Single Nucleotide Polymorphism Database, and 50 healthy controls from China origin (supplemental information, doi.org/10.5061/dryad.6cc5h8f).

Whole-exome sequencing bioinformatics was performed and confirmed that there were no other potential associated genes mutation in this pedigree. Therefore, these results indicate that the compound heterozygous mutations of CBS gene, c.551T>C and c.949A>G, which have not been previously reported, had a strong relationship with homocystinuria in this pedigree.