Early-onset Fahr's disease with atypical presentation of hypoglycemia and headache and fatal outcome in a 16-year-old male: A case report

Abstract

Fahr's disease, also known as primary familial brain calcification, is a progressive neurological disorder that follows an autosomal dominant inheritance pattern, characterized by calcifications primarily located within the basal ganglia of the brain. This condition typically affects middle-aged individuals, who present with a combination of neurological and psychiatric symptoms; however, this case report discusses a 16-year-old male patient. The patient initially exhibited general signs of infection, including fever and jaundice, before developing specific neurological symptoms, which progressed to systemic encephalopathy characterized by altered consciousness, seizures, and hypoglycemia, necessitating his admission to the ICU. Tragically, despite receiving intensive medical treatment, the patient succumbed to the disease, highlighting the challenges associated with diagnosing and managing Fahr's disease, particularly in younger patients.

Introduction

Fahr's disease, also referred to as primary familial brain calcification (PFBC), is a rare neurodegenerative condition characterized by the accumulation of calcium within neural tissues, primarily affecting the basal ganglia, thalami, and subcortical white matter [1]. This disorder is typically hereditary, with mutations occurring in specific genes such as SLC20A2, PDGFB, PDGFRB, and XPR1, which play roles in phosphate regulation and the integrity of the blood-brain barrier [2]. Although the exact mechanism by which these genetic mutations lead to the disease remains unclear, they disrupt the normal processes of calcium and phosphorus transport, resulting in calcium deposits in various brain regions, thereby impairing neuronal function and leading to a progressive decline in neurological capabilities [3].

Fahr's disease typically affects individuals in their third to fifth decades of life. Those affected commonly exhibit motor symptoms such as parkinsonism, dystonia, and tremors, along with cognitive deficits and various psychiatric manifestations, including depression, psychosis, and anxiety. Hence, the neuropsychiatric signs and symptoms can vary significantly among patients, influenced not only by the specific genetic mutations but also by differences in disease penetrance and expressivity. A range of neurological impairments may progressively worse, with most patients experiencing movement disorders, balance issues, and cognitive decline that can be severely disabling [4]. Cases of primary Fahr's disease are infrequent, and children who develop this condition often display a broad spectrum of clinical symptoms, complicating the diagnostic process. In younger individuals, the disease may present subtly, with initial symptoms often linked to systemic and neurological disturbances such as seizures, headaches, and cognitive issues that can hinder timely diagnosis. This variant differs from the adult-onset form, where patients may show mild psychiatric symptoms and less emphasis is placed on motor symptoms and disease duration tends to be shorter [5].

This report focuses on the case of a 16-year-old male patient, who displayed early manifestations of Fahr's disease that fell into the atypical category, marked by significant neurological decline and systemic symptoms such as fever and jaundice. His subsequent swift deterioration highlights the challenges in diagnosing this condition and underscores the potential for Fahr's disease to emerge in younger populations. Early detection is crucial for effective disease management, as undiagnosed cases can lead to unfavorable prognoses, as illustrated in this study.

Case presentation

A 16-year-old boy from Dinajpur who has received only 6 years of formal education struggles with his studies despite multiple attempts to enroll him in school. His family's socioeconomic background is challenging, with limited resources and educational support, which has likely hindered his academic progress. Additionally, both he and his younger siblings frequently complain of headaches, which may suggest underlying cognitive difficulties that further impede their ability to focus on studies. These factors together indicate that his limited education is likely influenced by a combination of socioeconomic challenges and potential cognitive impairments. He presented at the Zia Heart Foundation Hospital & Research Centre outpatient department, complaining of a headache, fever, red eyes, general body weakness, dark yellow urine, and poor appetite. No relevant neurological or psychiatric history was identified in the parents. Some of these mild symptoms were alleviated with medications such as vitamins, antipyretics, and normal saline to restore his energy, but no diagnosis was established at that moment. Clinically, nonspecific symptoms attributed to a viral illness were suspected.

In the subsequent month, new variables emerged; he began to exhibit neurological symptoms. He started experiencing headaches and displayed agitation, occasionally speaking with slurred speech, which, although brief, indicated underlying issues. As a result, he was admitted for further evaluation and monitoring. These symptoms prompted additional examinations and investigations, yet the underlying cause remained undetermined. Relevant findings done on 2022 included:

Hematologic tests indicated:

Hb: 10.5 g/dL (Normal 13-17 g/dL), Elevated ESR: 30 mm (Increased), RBC: 3.8 × 1012/L (Decreased), PCV: 32.9% (Decreased), Platelet: 1.43 lac (Decreased), MCH: 24.4 (Decreased), CRP: 58.9 mg/L (Normal 0.0-5.0)

Metabolic panel results showed:

Inorganic Phosphate: Normal, RBS: 5.9 mmol/L, Na+: 145 mmol/L, K+: 3.8 mmol/L, Cl-: 109 mmol/L, Calcium: 8.4 mmol/L Normal (8.4-10.4 mmol/L), Albumin: 5.2 g/L, FT4: Normal, TSH: 13.92 µIU/ml(Elevated), Intact PTH: 82.40 pmol/L (Normal: 9.0-80.00 pmol/L)

A comprehensive list of all investigations conducted for this patient is included in the supplementary file.

A month later, he experienced his first seizure, marking the onset of a more severe phase in his life. His seizures were initially managed with levetiracetam and phenytoin, but they soon became more frequent and intense. He reported experiencing vertigo, dizziness, and reduced sleep, which further obscured the clinical picture. Following an EEG (Fig. 1), it was confirmed that he was suffering from generalized tonic-clonic seizures.

Fig 1.

EEG showing generalized spike-and-wave discharges, 3 Hz spike-and-wave complexes & diffuse slowing waves suggesting GTCS (Generalized tonic-clonic seizure).

Condition worsened following next 2 months because he developed episodes where he would have to sleep much than usual while suffering from recurrent headaches. Such symptoms gave way to the later establishment of sub-clinical hypothyroidism based on the TSH levels and added to the complicating factors of the patient's case.

In his examination he was restless, could hardly speak properly and had several episodes of convulsions. He had no signs of Fahr's disease till now because he did not show a lot of distortions in his cognitive functioning and had no sign of shrinkage in his brain matter or serious psychiatric disorders. In the progression of his illness his neurological status became progressively more compromised. His Montreal cognitive assessment test showed score 22/30. He was showing spasticity, chorea, and rigidity in all extremities.

He also complained of recurrent fatigue and was diagnosed to be anemic throughout his hospital stay and had raised ESR suggestive of chronic inflammation. Tachycardia was observed at times, his other cardiopulmonary assessments being fairly normal. Biochemical parameters such as increased ESR levels, lowering of hemoglobin, and other characteristics showed that there was chronic inflammation. Actual blood chemistry, as it evolved during the consecutive days of the illness, did not reveal abnormal values of the serum calcium level.

After obtaining consent from patient party Spiral CT of brain was done which showed the bilateral calcifications in the basal ganglia, thalami, sub cortical white matter (Fig. 2). Radiologically we had other differentials like Wilson disease and Pseudohypoparathyroidism. But they were dismissed as metabolic panel didn't reveal any abnormality with copper or calcium. Final diagnosis made was Fahr's disease. Diagnostic criteria (Saleem et al.) used:

• •Bilateral calcification in Basal Ganglia visible on neuroimaging.
• •Exclude secondary causes of Fahr syndrome and biochemical abnormalities (infection, traumatic injury, metabolic, toxic).
• •Progressive neurological dysfunction involving movement and psychiatric disorders.

Fig. 2.

CT scan of the brain showing extensive calcifications in thalami, basal ganglia, subcortical white matter of both cerebral and cerebellar hemispheres.

He was put on anticonvulsants, calcium and vitamin supplements and supportive medications meant to handle the neurological manifestations of the patient. The above-mentioned interventions did not stabilize his condition; he continued to have convulsions and gradually developed worsening neurological manifestations.

A year after the family of patient one of the worst days in since he was found unconscious at his home and was immediately taken to the ICU. He did not follow basic commands and was apathetic to verbal commands and painful stimuli on arrival. Initial investigations showed low blood glucose levels which were critically low and referred to as hypoglycemia. Despite being administered intravenous glucose for management of the hypoglycemia there was little improvement in the neurological status of the patient.

Due to his condition, he was put on intubation and mechanical ventilation to assist him in maintaining adequate airway patency and in breathing accordingly. He was put on aggressive therapy, that included frequent blood glucose monitoring as well as other intensive care measures; however, his state worsened soon. Neurological evaluations carried out during his ICU course showed no neurologic improvement and follow-up imaging studies established the worsening of calcifications of the brain that could not have any reversible cause.

Finally, after a week of stay, he could not survive his illness and died in the ICU despite various attempts. These complications had been considered as the consequence of the primary Fahr's disease complicated by acute hypoglycemia and subsequent neurological deficits. This case clearly indicates the vicious and sometimes dangerous character of Fahr ‘s disease, especially at the young age.

Due to cultural belief parents didn't provide us consent to perform autopsy on this young lad. Our low resource setting country doesn't have means for genetic analysis for mutations or deletions in SLC20A2 or PDGFRB gene so it wasn't possible to do either.

Discussion

The case of early onset Fahr's disease in a male adolescent is remarkable, as this condition is generally observed in individuals during their fourth or fifth decade of life. The initial signs of Fahr's disease are exceedingly rare and are probably connected to a more rapid and aggressive clinical progression when compared to adult-onset cases. These early manifestations may be associated with genetic factors like mutations in the SLC20A2 gene, which disrupt phosphate metabolism, thereby accelerating the disease's progression in younger individuals [6].

The symptoms exhibited by the patient during the initial consultation included fever and jaundice-like symptoms, characterized by yellow urine, which are atypical for Fahr's disease and may have delayed the diagnosis. Systemic signs and symptoms are uncommon in Fahr's disease, with the predominant manifestations being neurological and psychiatric issues, including movement disorders, cognitive deficits, and neuropsychiatric symptoms such as anxiety, depression, and psychosis [7]. The occurrence of systemic symptoms in this instance may indicate a broader disturbance in metabolic processes, potentially linked to the genetic anomalies that are foundational to Fahr's disease.

The absence of prominent psychiatric symptoms, which are often seen in Fahr's disease, presented additional challenges for the diagnosis. Mood disorders, cognitive impairments, and psychotic behaviors are prevalent in adult cases of Fahr's disease, yet none of these were predominant in this patient's clinical presentation. This highlights the variability of clinical phenotypes and suggests that early onset may be characterized by a distinct clinical profile, featuring a greater proportion of motor symptoms and a more severe trajectory leading to neurological deficits [8].

This further complicates the condition, as evidenced by the presence of subclinical hypothyroidism in the patient. While endocrine dysfunction is not a hallmark of Fahr's disease, it may manifest due to gene mutations that influence metabolism in various ways. The relationship between Fahr's disease and endocrine dysfunction remains somewhat unclear, but it may be linked to alterations in calcium and phosphorus balance due to the involvement of phosphate transporter genes, including SLC20A2 and PDGFB [9].

This result suggests that Fahr's disease can lead to notable clinical decline, hypoglycemic episodes, and episodes of loss of consciousness, indicating that this illness may present with acute and potentially life-threatening manifestations. While hypoglycemia is not conventionally linked to Fahr's disease, this instance has shown that the condition might serve as a precursor to severe metabolic disturbances, often instigated by stress or illness. Such events could further aggravate the neurological condition, as illustrated by this case in which severe hypoglycemia led to significant neurological damage and ultimately resulted in death [10]. Thus, it is clear that urgent actions must be taken to ensure that Fahr's disease is diagnosed in its early stages, adopting a comprehensive approach, particularly concerning younger patients who exhibit symptoms that differ from those typically associated with this neurological condition. The presentation of this uncommon disease requires early imaging and genetic testing along with an increased awareness. Moreover, younger patients tend to experience a relatively rapid progression of the disease and thus necessitate highly individualized management strategies, including neurological, endocrinological, and metabolic support [11].

Overall, this case underscores the complexities surrounding Fahr's disease and prompts essential inquiries into the existing understanding of its pathophysiology and the treatment of early-onset cases. Enhanced awareness among clinicians could potentially facilitate earlier diagnoses for individuals with these disorders, leading to improved outcomes for the affected patients.

Conclusion

The patient discussed in this case report was also diagnosed with Fahr's disease, characterized by its atypical symptoms that develop rapidly in younger individuals, which suggests that healthcare professionals should take this condition into account when facing unexplained neurological and systemic issues. This instance serves as a clear illustration of early-onset Fahr's disease, which differs from the condition when it occurs in older adults and is typically associated with a broader array of symptoms that can include motor, cognitive, and sometimes systemic issues, such as hypoglycemia. The absence of classic signs of psychosis and the variability of initial symptoms contributed to prolonged misdiagnosis, exemplifying how the disease's progression can be atypical.

Fahr's disease presents a highly varied clinical profile, and its diagnosis often necessitates the exclusion of other similar neuropsychiatric conditions. Consequently, early involvement of the basal ganglia and other brain regions can result in significant motor and cognitive deficits, which may deteriorate sharply if left untreated. This case highlights the necessity for advanced neuroimaging techniques, particularly CT scans, which can aid physicians in differentiating Fahr's disease from other ailments that result in intracranial calcifications.

This is illustrated in this specific case, where the patient experienced rapid neurological decline, underscoring the importance of closely monitoring such individuals and developing a comprehensive, multidisciplinary management strategy. The involvement of an integrated care team, consisting of neurologists, endocrinologists, and geneticists, plays a crucial role in addressing the varied and complex needs of patients with Fahr's disease. This collaboration supports timely and accurate diagnosis, especially in instances where symptoms are ambiguous in young children, and aids in providing guidance to families due to the genetic nature of the disorder.

This case clearly illustrates that Fahr's disease is progressive rather than static, highlighting the urgent need to enhance clinicians' awareness of this condition. Further research into the molecular and precise etiological factors of early-onset Fahr's disease is essential for developing therapeutic strategies that may mitigate or alter the disease's progression. Given the potential to raise awareness and refine diagnostic methods, it is feasible to protect individuals from severe outcomes and improve the quality of life for those affected by Fahr's disease.

Ethical considerations

We have no obligation as per IRB as we didn't conduct any research on human/animal models. No conflict of interest present for this article and it adheres to the ethical guidelines. Every research paper which has been reviewed and data used have been properly cited with reference.

Generative AI use

For paraphrasing of citations limited use of Quillbot has been done and properly edited after review. We took help from ChatGPT for proofreading and improving flow of language.

Data sharing statement

Regarding the availability of the data of this study, the datasets are available from the corresponding author on reasonable request. Given the nature of the case report, consent for sharing data was obtained from the patient, and in the rare case that data is to be shared; it will only be done with the patient's identifiable information being removed. Users’ request should be accompanied by a statement of the motives behind the request and how the data will be used. The data will be disseminated in accordance with all the relevant ethical scenarios and the institutional norms.

Patient consent

Complete written informed consent was obtained from the patient for the publication of this study and accompanying images.