Difficult case of a rare form of familial Alzheimer’s disease with PSEN1 P117L mutation

Abstract

Less than 10% of Alzheimer’s disease (AD) cases are familial. Presenilin-1 (PSEN1) mutations are the most frequent aetiology and may be associated to atypical neurological manifestations. We report the case of a 27-year-old right-handed man, ensuing with mild cognitive impairment, motor discoordination and axial myoclonus after a parachute accident. At age 32 he was referred to our neurology clinic, presenting cognitive impairment, cerebellar syndrome, axial myoclonus and hypomimia, without other signs of parkinsonism. Because of absence of family history, he was worked up along the line of spinal ataxic disorders. Later, he developed pseudobulbar affect, cognitive deterioration, right upper limb paresis and spastic paraparesis. Subsequent investigation identified a PSEN1 P117L mutation and the diagnosis of autosomal dominant AD was made. This case illustrates the diagnostic challenge imposed by atypical presentation of de novo PSEN1 mutation, leading to unnecessary investigation. Genetic study might be essential for defining the diagnosis.

Background

This case is important because it shows the diagnostic difficulties of familial Alzheimer’s disease (AD) particularly when facing atypical presentations. The absence of family history contributed to the difficulty of the diagnosis, which ended in detection of a de novo mutation in presenilin-1 (PSEN1) gene.

To our knowledge, this is the sixth patient reported in the literature, carrying a PSEN P117L mutation.

Case presentation

In 2011, a 32 year-old man, presented to neurology consultation complaining of cognitive impairment.

He was right-handed, with 12 years of schooling, and was a former military parachutist. He had an unremarkable birth history, had a normal psychomotor development and did not have any history of previous illness, including neurological diseases. He was a smoker (15 pack-year) and denied any other substance abuse including alcohol and drugs.

There was no family history of dementia or other neurological or neuropsychiatric diseases. His parents were not consanguineous and he was not an adopted child.

The patient reported a parachute accident 7 years prior to consultation. The accident resulted in lumbar vertebral and sternal fractures but there was no traumatic brain injury. Despite chronic pain resulting from the accident, he kept working as military personnel until 2009. After the accident, he had multiple cognitive complaints including difficulty in thinking and planning, doing simple arithmetics, maintaining attention and remembering conversations. He also reported difficulty in finding words. Cognitive symptoms progressively worsened particularly when he lost his job, in 2009, but remained stable for some years afterwards. Besides these cognitive problems, his girlfriend mentioned he had occasional involuntary jerks of his trunk and some fine movements discoordination.

Neurological examination showed positive signs suggestive of cerebellar dysfunction, including scanning dysarthria, dysdiadochokinesia (worse on the left), overshooting on finger-nose test and pendular reflexes. He had hypomimia with upper and right gaze apraxia and delay in saccadic movements. Trunk myoclonus was observed. Cognitive assessment was performed, 5 years after his cognitive complaints started: he scored 21 on Mini Mental State Examination (with a total loss of evocation, loss of 3 points in calculation, did not recall the season or day of the month and did not know the floor he was in), with a global slowing in performance. The clock drawing test revealed difficulty in abstraction, as he had trouble in drawing clock hands, only drawing the hour hand correctly.

About 1 year later, he developed right hemiparesis (grade 4 in Medical Research Council Scale), and spasticity in both lower limbs (grade 1+ in Modified Ashworth Scale).

Ataxia and spasticity progressively worsened in the following years ensuing severe walking impairment. By the end of 2014, he was a wheelchair user. His cognitive symptoms further impaired and he developed pseudobulbar affect in 2015. He has also developed dysphagia.

Investigations

• Blood test (2011) including copper and ceruloplasmin, vitamin E, thyroid function, serologies (HIV, hepatitis C virus, hepatitis B virus, Lyme disease, syphilis, Epstein-Barr virus and Cytomegalovirus, anti-neuronal antibodies and alpha-fetoprotein were normal or negative.

• CSF study (2012) was unremarkable.

• Spinal cord MRI (2010) was normal.

• Brain MRI (2012) showed a discrete atrophy, without focal predominance, namely cerebellar, hippocampus or brainstem (figure 1).

• Electroencephalogram (2011), electromyography (2011), somatosensory (2011) and visual (2016) evoked potentials were normal.

• Neuropsychological evaluation (2011) showed multi-domain alteration with characteristics of a corticosubcortical pattern, suggesting cognitive impairment; a re-evaluation (2013) evidenced deterioration of cognitive function.

• Genetic study for X-fragile, neuroacanthocytosis, SCA6, SCA14, SCA16, SCA17 and Friedreich’s ataxia (2012–2015) was negative.

Figure 1.

Brain MRI showing diffuse discrete atrophy, without focal predominance.

Genetic study for dementia (2015) showed a mutation in PSEN1 gene—PSEN p.P117L.

Differential diagnosis

1. Traumatic brain injury: the patient relates the beginning of cognitive complaints with the accident. Nevertheless, he does not report the existence of head trauma and the disorder is progressive despite the absence of history of consecutive head trauma.

2. Friedreich’s ataxia: the most common hereditary ataxia, thus being part of the differential diagnosis, nevertheless, in this case, the late age of onset is atypical, as are the neurological findings of normal proprioceptive and deep tendon reflexes.

3. Spinocerebellar ataxias (SCA): particularly those that manifest with myoclonus (SCA2, SCA14, SCA19/22) and spastic paraparesis (SCA1, SCA3, SCA23, SCA28), with a later age of onset, or autosomal recessive SCA should also be considered in the differential diagnosis.

4. Isolated vitamin E deficit: a treatable cause of ataxia and hence should be considered as a differential diagnosis. Abnormalities relating vitamin E deficiency are usually progressive from hyporeflexia, ataxia, limitation in upward gaze, and strabismus to long-tract defects, including visual-field constriction and profound muscle weakness. Blindness, cardiac arrhythmia and dementia may occur in patients in whom vitamin E deficiency has been prolonged and severe.

5. Mitochondrial disease associated with ataxia and myoclonus should also be considered, particularly ataxic neuropathy spectrum disorders (including mitochondrial recessive ataxia syndrome and sensory ataxic neuropathy, dysarthria, and ophthalmoparesis), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke, myoclonic epilepsy with ragged red fibres and neuropathy, ataxia and retinitis pigmentosa.

6. Progressive myoclonic epilepsies, include neuronal ceroid lipofuscinosis, Unverricht-Lundborg disease and sialidosis types 1 and 2.

Treatment

The patient was initially treated with baclofen 10 mg two times per day and later tizanidine 2 mg two times per day for spasticity and with sertraline 50 mg for depressive symptoms.

Later when the diagnosis of Alzheimer’s disease (AD) was made, 9 years after the beginning of cognitive decline, he started rivastigmine 9.5 mg followed by memantine 20 mg.

Outcome and follow-up

Patient’s global health status progressively worsened, he became dependent for all daily activities and is currently bedridden.

The treatment with rivastigmine and memantine was started in a very advanced phase of the disease and there was no subjective improvement in patient status. By this time, he was no longer collaborative enough to perform neuropsychological evaluation.

None of the patient’s relatives consented to perform genetic testing, so the mutation’s presence in the family is unknown.

Discussion

PSEN P117L is a mutation in PSEN1 gene, a known cause of exceptionally severe FAD, only described in five patients, four of those belonging to the same family.^1–3 Mean age of onset is 31.6 years, in one of the described cases as early as 28 years of age. Table 1 describes the main clinical and radiological characteristics of these cases.

Table 1.

Clinical and radiological characteristics of previous reported patients with PSEN P117L mutation and our patient

Patient	11 2	21 2	31 2	41 2	53	Our patient
Gender	Male	Male	Female	Female	Male	Male
Age of onset	32	24	32	33	38	25
Presenting cognitive complaints	Memory loss	Memory loss Mood disturbance	Memory loss	Memory loss Mood disturbance	Memory loss Mood disturbance Non-fluent aphasia	Memory loss Non-fluent aphasia
Atypical clinical features	None reported	None reported	Myoclonus rigidity	Myoclonus rigidity	Decomposed pursuit eye movements Ataxia Extrapyramidal rigidity Myoclonic jerks Psychosis Generalised seizures	Cerebellar syndrome Spastic paraparesis Hypomimia Axial myoclonus
Radiological characteristics	Unknown	Unknown	Brain MRI: diffuse brain atrophy	Brain CT: diffuse brain atrophy	Brain SPECT-SPM: significant reduction of blood flow in left and right parietal, temporal and occipital cortex, including the precuneus, the posterior cingulate gyrus; initial involvement of the left frontal regions	Brain MRI: discrete atrophy without focal predominance
Age of death	39	28	35	37	Unknown	Patient is alive

Our patient presented a de novo mutation, with an extremely young age of symptoms onset and an atypical clinical picture with initial predominance of cerebellar syndrome, spastic paraparesis, axial myoclonus and hypomimia. All these factors contributed to a long delay in diagnosis, that was made in a late phase of disease course.

A few mutations in PSEN1 gene have been described with spastic paraparesis,^4–12 but only three with ataxia.^13–15

The early diagnosis of these cases might allow enrolment in ongoing studies like the ones developed by the Dominantly Inherited Alzheimer Network.¹⁶ This group follows patients diagnosed with familial AD in order to develop a better understanding of disease evolution and also includes patients in clinical trials of drugs that could potentially change the course of the disease.

Early diagnosis of familial AD might also select candidates for tests for pre-implantation genetic diagnosis technique for in vitro fertilisation or diagnosis during pregnancy (eg, amniotic fluid sampling or chorionic villus sampling).

Patient’s perspective.

Mother’s perspective: “It’s been very difficult to deal with my son’s health worsening; this is not supposed to happen. I don’t know how the future will be and that’s desperating!”

Learning points.

• Familial Alzheimer’s disease (AD) might have atypical clinical presentation.

• The final diagnosis may only be reached by genetic testing especially when there is no family history, for example, de novo mutation or adopted child.

• Diagnosing these atypical cases is important, as it can have consequences regarding family planning and may potentially allow the inclusion of patients in clinical trials.

• Genetic testing for familial AD should be considered when young patients have cognitive complaints accompanied with cerebellar syndrome, spastic paraparesis, axial myoclonus and hypomimia.