LOTS and neuromuscular disease

In our cohort, four patients were initially diagnosed with a possible neuromuscular or motoneuron (MN) disease (Table 1). Patient 5 was a 61 year old woman of AJ ancestry who developed weakness in her lower limbs in her 20s, particularly ascending stairs. Electromyography/nerve conduction study (EMG/NCS) demonstrated an axonal neuropathy that led to an initial diagnosis of Amyotrophic Lateral Sclerosis (ALS) or Spinal Muscular Atrophy (SMA) and subsequently of muscular dystrophy. In the following years her gait worsened and she developed slurred speech. At age 54, enzymatic testing eventually confirmed the diagnosis of LOTS. Patient 3 was a non-AJ, 43-year-old woman who presented with bilateral leg weakness in her 20s. She was initially diagnosed with Lyme disease. She received the final diagnosis of LOTS seven years later. Patient 7 was a 36-year-old AJ-man who developed difficulties with transfers and frequent falls in his early 20s. He was evaluated only at the age of 29. An EMG/NCV showed neuropathy with active and chronic denervation and he was referred to an ALS center. LOTS was diagnosed at age of 31. In retrospect, he had transitory jaundice right after birth and slurred speech since the age of 3, requiring speech therapy. Although he played numerous sports as a child, he was clumsier compared to his peers. Patient 8 was a 30-year-old, AJ-woman with a kinetic tremor of the hands since her first decade. At age of 18 she was diagnosed with essential tremor, treated with clonazepam and propranolol with partial benefit. Her exam was notable for proximal weakness. An EMG/NCV showed a chronic motor neuronopathy mostly affecting her lower limbs. A nerve biopsy showed severe, chronic, neurogenic changes. Late onset SMA was diagnosed. She then developed cerebellar signs, including ataxic speech, dysmetria and wide based gait, but it was only at age of 26 that she received a diagnosis of LOTS.

In the literature, 42 single case reports of LOTS presented a prominent motoneuronal phenotype [13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28] (Table 2). Similarly to our cases, the age of onset was mostly in the second decade, except for few exceptions [21, 23, 24, 25]. The diagnosis was delayed by about 10 years from the age of onset, in line with other cases of LOTS, with an almost equal male/female ratio. Gly269Ser, the most common variant of HEXA reported in patient with LOTS, was present in almost all the cases of this cohort where genotype was tested. About half of these patients were of AJ ancestry, although ethnicity was not reported in all published cases. Different from the classical form of ALS, where the onset of disease is heralded by asymmetric and distal atrophy and weakness, the majority of LOTS patients presented symmetric proximal weakness (brachial triceps and thigh quadriceps), with prominent involvement of the lower limbs. In adjunct, these cases still exhibited cerebellar and psychiatric symptoms as well (Figure 1, Video 1). The “triceps sign” is a distinctive features of LOTS and consists in a selective weakness of forearm extension and loss of triceps reflex, with retained forearm flexion and the other reflexes in the upper limbs. Cognitive impairment, when present, was typically mild and usually affecting memory. Differently from the classical motor neuron diseases, ocular movements were variably impaired as well as other bulbar functions. No systemic symptoms or significant family history were reported. Brain MRI always showed cerebellar atrophy, irrespective of clear cerebellar signs. Moreover, in most patients, tremor and ataxic gait presented many years after the initial onset of the symptoms, usually in their 30s [11]. In this cohort of patients atypical features have been reported, such as mild chorea, progressive supranuclear gaze palsy, bilateral cranial VI nerve paralysis, stimulus sensitive myoclonus, bradykinesia, dystonia and dyskinesia, as well as sensory impairment [13, 14, 17, 19, 21, 24, 28]. Four cases presented almost pure MN phenotypes, with involvement of both the upper and lower MN [23]. In all these cases stuttering was described, while only one cases was diagnosed with psychotic symptoms, and one case also presented resting tremor [23].

In the literature different studies screened populations of patients with pure MND but failed to identify mutations of the HEXA gene [29, 30, 31]. The presence of atypical features (i.e. associated cerebellar signs), and/or predominant proximal weakness (triceps and quadriceps weakness) should prompt adding LOTS in the list of differential diagnosis in these cases.

LOTS and psychiatric abnormalities

Psychiatric presentations are common among patients with LOTS. A seminal work by Navon et al. calculated an incidence of 28% of psychiatric features in patients with LOTS [23]. They identified two major phenotypes: depression with psychotic features, and disorganized schizophrenia, both associated with different degrees of cognitive deterioration [23]. However, later reports indicated an incidence of psychiatric features in up to 50% of cases [32, 33]. In our cohort, three cases presented with prominent psychiatric manifestations. Patient 6 is a 52-year-old, AJ-man who presented with a psychotic episode at age 27. In retrospect, he noted weakness in his lower limbs since the age of 25 manifesting as difficulty shifting his legs while driving a bus, as well as difficulties focusing since he was in school. His motor symptoms progressed but a diagnosis of LOTS was confirmed much later, at age 47. Patient 9 is a 23-year-old, AJ-woman initially diagnosed with LOTS during a prenatal screening. At age 23, she had a manic episode characterized by decreased sleep, grandiosity, depersonalization and paranoid delusions that led to a brief psychiatric hospitalization. She was treated with lithium, carbamazepine and clonazepam and was able to return to college. However, she was already exhibiting slurred speech (requiring speech therapy), cerebellar signs, and proximal muscle weakness. Looking back, since high school she had bilateral leg weakness and balance impairment, with difficulties keeping up the pace when walking with peers and tended away from athletic activities. Similarly, patient 2 presented in her early twenties a maniac episode characterized by sleep deprivation, impulsive money spending, increased sexual activities with promiscuity that led to the diagnosis of bipolar disorder, treated with aripiprazole, fluoxetine, and bupropion. LOTS was diagnosed only a decade later due to the concomitant cerebellar symptoms (as described below). In addition to mood disorders and psychosis, a significant number of case in our cohort (5 out of 9 cases) also presented attention deficit disorders since their early ages often associated with learning difficulties. Disinhibition was present in 67% of cases as well.

To date, ten cases of LOTS have been reported in the literature with a psychiatric impairment as the first symptom [23, 25, 28, 33, 33, 34, 35, 36, 37, 38] (Table 2). Interestingly, upon further review, some of these patients were already exhibiting other features, such as speech or gait impairment, even before the psychiatric manifestations [25, 33, 34, 35, 36]. In almost all the cases psychiatric symptoms became evident in the late teen ages or early 20s.

Seizures preceding psychiatric abnormalities were reported only in one case with onset at 20 years of age, representing the first manifestation of LOTS [35]. Auditory hallucinations have been reported as well [22]. One report described a woman who experienced post-partum psychosis, which resolved within one month after treatment with lithium [39].

Based on literature review, there is a significant delay in the diagnosis in patients presenting with predominant psychiatric manifestations (mean years of delay in diagnosis is 11.42 years, Table 2). The reported male to female ratio is 6:3, although the number of patients is still very low to drive conclusive observations (Table 2).

LOTS and cerebellar impairment

Although cerebellar atrophy and cerebellar signs are well described in both TSD and in LOTS, few cases have been reported as pure cerebellar syndromes and yet those are still often misdiagnosed for other forms of inherited ataxia syndromes. In line with this observation, in our cohort we identified only one patient presenting with prominent cerebellar features. Patient 2 is 40-year-old, AJ-woman who started presenting progressive gait and balance impairment as well as slurred speech and dysphagia since childhood. These symptoms were initially attributed to the sequelae of a presumed cerebral palsy. At age 25 she was diagnosed with bipolar disorder. A brain MRI at age 30 showed cerebellar atrophy and spinocerebellar atrophy (SCA) was suspected. The rapid progression of her symptoms prompted further diagnostic workup and a reduced HEXA activity was detected. Genetic analysis confirmed a compound heterozygote variant in the HEXA gene (c.805G>A/c.1421+1G>C).

Seventeen cases have been reported in the literature were patients were initially diagnosed with Friedreich ataxia, spinocerebellar ataxia or tremor [25, 28, 40, 41, 42] (Table 2). In these cases age of onset was mostly in the first decade, therefore slightly earlier compared to patients presenting with MND or psychiatric symptoms, with only few cases with onset in the second or third decades [25, 28]. In one of these cases the symptomatology presented as an isolated action and resting tremor, and as tremor associated with psychotic symptoms in the other one [25]. There was an equal distribution between males and females. The delay of diagnosis is much longer compared to the other phenotypes (16.1 years on average). 64.7% of the cases were of AJ ancestry. Only 29% of the cases presented initially with psychiatric features, while almost half of the cerebellar cases also had pes cavus, which is interestingly is more frequently associated with Sandoff disease.

LOTS and stuttering

Interestingly in a small subset of cases in the literature (2 reports, describing a total of 6 cases) LOTS mainly manifested with stuttering of the speech [43, 44] (Table 2). Speech abnormalities are frequently a very prodromal symptom of LOTS, although most of the time they go undiagnosed because of the very low specificity of the symptoms (Video 1). In most of the reported cases presenting with stuttering, this symptom presented during elementary school. In only one case the symptoms manifested when the patient was 16 years old, associated with dysarthria [44]. Females seem to be affected by this phenotype five time more than males, although the overall population is very small. Those cases are mostly European and with no AJ ancestry. The delay in diagnosis range from 3 to 16 years. Interestingly, all the cases presented with a similar timeline: stuttering presented in the first decade followed by weakness and clumsiness in adolescence (in 2 patients) and then psychiatric impairment in their twenties. Ataxia, dysarthria and pyramidal signs presented later. Tremor was present only in a minority of the cases. These patients did not reported other characteristic features.

Interestingly, other late-onset forms of lysosomal storage disorders may also present with stutter, especially GM1 gangliosidosis, metachromatic leukodystrophy, Krabbe disease and Niemann–Pick type C, all of which have overlapping clinical features with LOTS [43]. The possible correlation between lysosomal storage disorders and stuttering is not clear yet.

None of our patients specifically stated that they had stuttering as part of their speech impairment either now or in retrospect. Their speech was characterized as ataxic dysarthria, however, stuttering was apparent on exam in 3 of them.

Other features

Other common features of LOTS are usually identified after the diagnosis is made. Eye movement abnormalities have been extensively described and analyzed in this disorder consisting in a disruption of the normal saccadic system, with hypometria, transient decelerations, and premature termination [45] (Video 1). Nystagmus and impaired saccades have been reported in 21% of the cases where eye movements were assessed [17, 18, 33, 40, 41, 46]. Loss of vertical eye movements has been described in 8 cases in the literature, often incomplete and affecting the upbeat gaze [17, 25, 36, 40, 46, 47, 48]. The presence of supranuclear ophthalmoplegia is associated with a very wide age of onset and with either ataxic, psychiatric or neuromuscular impairments at presentation.

Another recurrent features in LOTS is the presence of pes cavus, not necessarily associated with the neuromuscular phenotype [25, 40, 41, 49]. While Shapiro et al. described a prevalence of 27% of axonal peripheral neuropathy in a cohort of thirty patients with LOTS, this feature has not been frequently observed in the clinical evaluation of the cases reported in the literature, where only two cases presented sensory symptoms, and other two were diagnosed with peripheral neuropathy [19, 24, 42, 48, 50].

Parkinsonism/basal ganglia phenotypes

Different movement disorders have been associated with LOTS in the literature. In the cohort described by Argov et al. (1984), one patients initially presented with a neuromuscular phenotype during adolescence, then complicated by cerebellar signs and tremor [25]. After two decades from the onset he developed rigidity and bradykinesia, with dramatic response to levodopa but early manifestation of motor fluctuations and dyskinesia, after only two years [51]. In the same paper, the father of one patient, who had intermediate deficiency of hexosaminidase activity, developed Parkinson’s disease at age 45, and 20 years later developed severe cognitive impairment [25]. Autoptic cases of patients diagnosed with LOTS showed different degrees of degeneration of the basal ganglia, particularly in the substantia nigra [52].

Dystonia can be part of LOTS but has never been described as an isolated feature [28, 35, 37, 49, 53]. In these cases, dystonia usually involves the limbs, but facial grimace or speech impairment have been reported as well [21, 40, 46]. Chorea and stimulus sensitive myoclonus were reported in few isolated cases [13, 19, 48, 54].